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  • 1.
    Gao, Tianle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Chinese Acad Med Sci, Inst Mat Med, Beijing, Peoples R China.
    Ma, Haisha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergman, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch2018In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 138, no 11, p. 2405-2411Article in journal (Refereed)
    Abstract [en]

    Itch is a somatosensory modality that serves to alert an organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch, whereas chemical itch was unaffected. We examined the effect of activating the NPY/Y-1 receptor system on scratch behavior in mice. We found that intrathecal administration of the Y-1 agonist [Leu(31), Pro(34)]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck compared with saline treatment, indicating that activation of the spinal NPY/Y-1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y-1 antagonist BIBO3304. Intrathecal application of the native nonselective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y-1 system dampens both mechanically and chemically induced scratching and hence is shared by the two submodalities of itch.

  • 2.
    Hao, Yan
    et al.
    KTH Royal Inst Technol, Dept Chem, Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Yang, Wenxing
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Emory Univ, Dept Chem, 1515 Dickey Dr NE, Atlanta, GA 30322 USA.
    Karisson, Martin
    KTH Royal Inst Technol, Dept Chem, Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Cong, Jiayan
    KTH Royal Inst Technol, Dept Chem, Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Wang, Shihuai
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Li, Xing
    East China Univ Sci & Technol, Inst Fine Chem, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Hua, Jianli
    East China Univ Sci & Technol, Inst Fine Chem, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China.
    Kloo, Lars
    KTH Royal Inst Technol, Dept Chem, Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Boschloo, Gerrit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Efficient Dye-Sensitized Solar Cells with Voltages Exceeding 1 V through Exploring Tris(4-alkoxyphenyl)amine Mediators in Combination with the Tris(bipyridine) Cobalt Redox System2018In: ACS ENERGY LETTERS, ISSN 2380-8195, Vol. 3, no 8, p. 1929-1937Article in journal (Refereed)
    Abstract [en]

    Tandem redox electrolytes, prepared by the addition of a tris(p-anisyl)amine mediator into classic tris(bipyridine)cobalt-based electrolytes, demonstrate favorable electron transfer and reduced energy loss in dye-sensitized solar cells. Here, we have successfully explored three tris(4-alkoxyphenyl)-amine mediators with bulky molecular structures and generated more effective tandem redox systems. This series of tandem redox electrolytes rendered solar cells with very high photovoltages exceeding 1 V, which approaches the theoretical voltage limit of tris(bipyridine)cobalt-based electrolytes. Solar cells with power conversion efficiencies of 9.7-11.0% under 1 sun illumination were manufactured. This corresponds to an efficiency improvement of up to 50% as compared to solar cells based on pure tris(bipyridine)cobalt-based electrolytes. The photovoltage increases with increasing steric effects of the tris(4-alkoxyphenyl)amine mediators, which is attributed to a retarded recombination kinetics. These results highlight the importance of structural design for optimized charge transfer at the sensitized semiconductor/electrolyte interface and provide insights for the future development of efficient dye-sensitized solar cells.

  • 3.
    Huang, Jing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Gilbert Gatty, Mélina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Pati, Palas Baran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Etman, Ahmed S.
    Stockholm Univ, Dept Mat & Environm Chem MMK, SE-10691 Stockholm, Sweden.
    Tian, Lei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Sun, Junliang
    Stockholm Univ, Dept Mat & Environm Chem MMK, SE-10691 Stockholm, Sweden.
    Hammarström, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Tian, Haining
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Covalently linking CuInS2 quantum dots with a Re catalyst by click reaction for photocatalytic CO2 reduction2018In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 47, no 31, p. 10775-10783Article in journal (Refereed)
    Abstract [en]

    Covalently linking photosensitizers and catalysts in an inorganic-organic hybrid photocatalytic system is beneficial for efficient electron transfer between these components. However, general and straightforward methods to covalently attach molecular catalysts on the surface of inorganic semiconductors are rare. In this work, a classic rhenium bipyridine complex (Re catalyst) has been successfully covalently linked to the low toxicity CuInS2 quantum dots (QDs) by click reaction for photocatalytic CO2 reduction. Covalent bonding between the CuInS2 QDs and the Re catalyst in the QD-Re hybrid system is confirmed by UV-visible absorption spectroscopy, Fourier-transform infrared spectroscopy and energy-dispersive X-ray measurements. Time-correlated single photon counting and ultrafast time-resolved infrared spectroscopy provide evidence for rapid photo-induced electron transfer from the QDs to the Re catalyst. Upon photo-excitation of the QDs, the singly reduced Re catalyst is formed within 300 fs. Notably, the amount of reduced Re in the linked hybrid system is more than that in a sample where the QDs and the Re catalyst are simply mixed, suggesting that the covalent linkage between the CuInS2 QDs and the Re catalyst indeed facilitates electron transfer from the QDs to the Re catalyst. Such an ultrafast electron transfer in the covalently linked CuInS2 QD-Re hybrid system leads to enhanced photocatalytic activity for CO2 reduction, as compared to the conventional mixture of the QDs and the Re catalyst.

  • 4.
    Huang, Jing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. KTH Royal Inst Technol, Sch Engn Sci, Dept Appl Phys, Stockholm, Sweden.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Tian, Lei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Pati, Palas Baran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Etman, Ahmed S.
    Stockholm Univ, Dept Mat & Environm Chem MMK, SE-10691 Stockholm, Sweden.
    Sun, Junliang
    Stockholm Univ, Dept Mat & Environm Chem MMK, SE-10691 Stockholm, Sweden.
    Hammarström, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Tian, Haining
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    A heavy metal-free CuInS2 quantum dot sensitized NiO photocathode with a Re molecular catalyst for photoelectrochemical CO2 reduction2019In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 55, no 55, p. 7918-7921Article in journal (Refereed)
    Abstract [en]

    Heavy metal-free CuInS2 quantum dots (QDs) were employed as a photosensitizer on a NiO photocathode to drive an immobilized molecular Re catalyst for photoelectrochemical CO2 reduction for the first time. A photocurrent of 25 mu A cm(-2) at -0.87 V vs. NHE was obtained, providing a faradaic efficiency of 32% for CO production.

  • 5.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Unexpected multiplicity of QRFP receptors in early vertebrate evolution2014In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, p. 337-Article in journal (Refereed)
    Abstract [en]

    The neuropeptide QRFP, also called 26RFa, and its G protein-coupled receptor GPR103 have been identified in all vertebrates investigated. In mammals, this peptide-receptor pair has been found to have several effects including stimulation of appetite. Recently, we reported that a QRFP peptide is present in amphioxus, Branchiostoma floridae, and we also identified a QRFP receptor (QRFPR) that mediates a functional response to sub-nanomolar concentrations of the amphioxus peptide as well as short and long human QRFP (Xu et al., submitted). Because the ancestral vertebrate underwent two tetraploidizations, it might be expected that duplicates of the QRFP gene and its receptor gene may exist. Indeed, we report here the identification of multiple vertebrate QRFPR genes. Three QRFPR genes are present in the coelacanth Latimeria chalumnae, representing an early diverging sarcopterygian lineage. Three QRFPR genes are present in the basal actinopterygian fish, the spotted gar. Phylogenetic and chromosomal analyses show that only two of these receptor genes are orthologous between the two species, thus demonstrating a total of four distinct vertebrate genes. Three of the QRFPR genes resulted from the early vertebrate tetraploidizations and were copied along with syntenic neuropeptide Y receptor genes. The fourth QRFPR gene may be an even older and distinct lineage. Because mammals and birds have only a single QRFPR gene, this means that three genes have been lost in these lineages, and at least one of these was lost independently in mammals and birds because it is still present in a turtle. In conclusion, these results show that the QRFP system gained considerable complexity in the early stages of vertebrate evolution and still maintains much of this in some lineages, and that it has been secondarily reduced in mammals.

  • 6.
    Leandri, Valentina
    et al.
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Raffaella, Angela
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Pizzichetti, Pia
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Uppsala Univ, Angstrom Lab, Dept Chem, Div Phys Chem,Ctr Mol Devices, Box 523, SE-75120 Uppsala, Sweden.
    Franchi, Daniele
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Organ Chem, SE-10044 Stockholm, Sweden.
    Zhang, Wei
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Benesperi, Iacopo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Uppsala Univ, Angstrom Lab, Dept Chem, Div Phys Chem,Ctr Mol Devices, Box 523, SE-75120 Uppsala, Sweden.
    Freitag, Marina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Uppsala Univ, Angstrom Lab, Dept Chem, Div Phys Chem,Ctr Mol Devices, Box 523, SE-75120 Uppsala, Sweden.
    Sun, Licheng
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Organ Chem, SE-10044 Stockholm, Sweden;DUT, DUT KTH Joint Res Ctr Mol Devices, State Key Lab Fine Chem, Dalian 116024, Peoples R China.
    Kloo, Lars
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Gardner, James M.
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Div Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Exploring the Optical and Electrochemical Properties of Homoleptic versus Heteroleptic Diimine Copper(I) Complexes2019In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 58, no 18, p. 12167-12177Article in journal (Refereed)
    Abstract [en]

    Due to ligand scrambling, the synthesis and investigation of the properties of heteroleptic Cu(I) complexes can be a challenging task. In this work, we have studied the optical and electrochemical properties of a series of homoleptic complexes, such as [Cu(dbda)(2)](+), [Cu(dmp)(2)](+), [Cu(Br-dmp)(2)](+), [Cu(bcp)(2)](+), [Cu(dsbtmp)(2)](+), [Cu(biq)(2)](+), and [Cu(dap)(2)](+) in solution, and those of their heteroleptics [Cu(dbda)(dmp)](+), [Cu(dbda)(Br-dmp)](+), [Cu(dbda)(bcp)](+), [Cu(dbda)(dsbtmp))(+), [Cu(dbda)(biq)](+), [Cu(dbda)(dap)](+) adsorbed on the surface of anatase TiO2 (dbda = 6,6'-dimethyl-2,2'-bipyridine-4,4'-dibenzoic acid; dmp = 2,9-dimethyl-1,10-phenanthroline; Br-dmp = 5-bromo 2,9-dimethyl-1,10-phenanthroline; bcp = bathocuproine or 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline; dsbtmp = 2,9-di(sec-butyl)-3,4,7,8-tetramethyl-1,10-phenanthroline; biq = 2,2'-biquinoline; dap = 2,9-dianisyl-1,10-phenanthroline). We show that the maximum absorption wavelengths of the heteroleptic complexes on TiO2 can be reasonably predicted from those of the homoleptic complexes in solution through a simple linear relation, whereas the prediction of their redox properties is less trivial. In the latter case, two different linear patterns emerge: one including the ligands bcp, biq, and dap and another one including the ligands dmp, Br-dmp, and dsbtmp. We offer an interpretation of the data based on the chemical structure of the ligands. On one hand, ligands bcp, biq, and dap possess a more extended pi-conjugated system, which gives a more prominent contribution to the overall redox properties of the ligand dbda. On the other hand, the ligands dmp, Br-dmp, and dsbtmp are all phenanthroline-based containing alkyl substituents and contribute less than dbda to the overall redox properties.

  • 7.
    Shebanits, Kateryna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University.
    Vasile, Silvana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Functional characterization in vitro of twelve naturally occurring variants of the human pancreatic polypeptide receptor NPY4R2019In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, article id 101933Article in journal (Refereed)
    Abstract [en]

    Obesity has become a global health problem and therefore understanding of the mechanisms regulating hunger and satiety is of utmost importance for the development of new treatment strategies. The Y4 receptor, encoded by the NPY4R gene, and its ligand pancreatic polypeptide (PP) have been reported to mediate a satiety signal. Multiple genetic studies have reported an association between NPY4R copy number and body weight. The gene also displays several SNP variants, many of which lead to amino acid differences, making it interesting to study. We have investigated the functional properties of 12 naturally occurring amino acid sequence variants of the Y4 and interpret the results in relation to sequence conservation and our structural model of the human Y4 receptor protein. Three receptor variants, Cys201(ECL2)Tyr, Val271(6.41)Leu and Asn318(7.49)Asp, were found to completely lose functional response, measured as inositol phosphate turnover, while retaining membrane expression. They display high sequence conservation and have important roles in the receptor structure. For two receptor variants the potency of PP was significantly decreased, Cys34(NT)Ser (EC50 = 2.9 nM, p < .001) and Val135(3.46)Met (EC50 = 3.0 nM, p < .01), compared to wild-type Y4 (EC50 = 0.68 nM). Cys34 forms a disulphide bond with Cys298, linking the N-terminal part to ECL3. The Val135(3.46)Met variant has an amino acid replacement located in the TM3 helix, one helix turn above the highly conserved ERH motif. This position has influence on the network of residues involved in receptor activation and subsequent inactivation. Sequence conservation and the structural model are consistent with these results. The remaining seven positions had no significant effect on the receptor's functional response compared to wild-type Y4. These positions display more variation during evolution. Understanding of the interactions between the Y4 receptor and its native PP agonist and the effects of amino acid variation on its functional response will hopefully lead to future therapeutic possibilities.

  • 8.
    Sundström, Görel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Tomas A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Heldin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b2013In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 7, article id 29Article in journal (Refereed)
    Abstract [en]

    The neuropeptide Y (NPY) system influences numerous physiological functions including feeding behavior, endocrine regulation, and cardiovascular regulation. In jawed vertebrates it consists of 3-4 peptides and 4-7 receptors. Teleost fishes have unique duplicates of NPY and PYY as well as the Y8 receptor. In the zebrafish, the NPY system consists of the peptides NPYa, PYYa, and PYYb (NPYb appears to have been lost) and at least seven NPY receptors: Y1, Y2, Y2-2, Y4, Y7, Y8a, and Y8b. Previously PYYb binding has been reported for Y2 and Y2-2. To search for peptide-receptor preferences, we have investigated PYYb binding to four of the remaining receptors and compared with NPYa and PYYa. Taken together, the most striking observations are that PYYa displays reduced affinity for Y2 (3 nM) compared to the other peptides and receptors and that all three peptides have higher affinity for Y4 (0.028-0.034 nM) than for the other five receptors. The strongest peptide preference by any receptor selectivity is the one previously reported for PYYb by the Y2 receptor, as compared to NPY and PYYa. These affinity differences may be helpful to elucidate specific details of peptide-receptor interactions. Also, we have investigated the level of mRNA expression in different organs using qPCR. All peptides and receptors have higher expression in heart, kidney, and brain. These quantitative aspects on receptor affinities and mRNA distribution help provide a more complete picture of the NPY system.

  • 9.
    Sundström, Görel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larsson, Tomas A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Heldin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Conlon, JM
    Dept of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University .
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Denver, RJ
    Department of Molecular, Cellular and Developmental Biology, The University of Michigan, 3065C Kraus Building, Ann Arbor, MI 48109-1048, USA.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 177, no 3, p. 322-331Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y and its related peptides PYY and PP (pancreatic polypeptide) are involved in feeding behavior, regulation of the pituitary and the gastrointestinal tract, and numerous other functions. The peptides act on a family of G-protein coupled receptors with 4-7 members in jawed vertebrates. We describe here the NPY system of the Western clawed frog Silurana (Xenopus) tropicalis. Three peptides, NPY, PYY and PP, were identified together with six receptors, namely subtypes Y1, Y2, Y4, Y5, Y7 and Y8. Thus, this frog has all but one of the ancestral seven gnathostome NPY-family receptors, in contrast to mammals which have lost 2-3 of the receptors. Expression levels of mRNA for the peptide and receptor genes were analyzed in a panel of 19 frog tissues using reverse transcriptase quantitative PCR. The peptide mRNAs had broad distribution with highest expression in skin, blood and small intestine. NPY mRNA was present in the three brain regions investigated, but PYY and PP mRNAs were not detectable in any of these. All receptor mRNAs had similar expression profiles with high expression in skin, blood, muscle and heart. Three of the receptors, Y5, Y7 and Y8, could be functionally expressed in HEK-293 cells and characterized with binding studies using the three frog peptides. PYY had the highest affinity for all three receptors (K(i) 0.042-0.34 nM). Also NPY and PP bound to the Y8 receptor with high affinity (0.14 and 0.50 nM). The low affinity of NPY for the Y5 receptor (100-fold lower than PYY) differs from mammals and chicken. This may suggest a less important role of NPY on Y5 in appetite stimulation in the frog compared with amniotes. In conclusion, our characterization of the NPY system in S. tropicalis with its six receptors demonstrates not only greater complexity than in mammals but also some interesting differences in ligand-receptor preferences.

  • 10.
    Wang, Linqin
    et al.
    KTH Royal Inst Technol, Dept Chem, Organ Chem, SE-10044 Stockholm, Sweden.
    Zhang, Jinbao
    Monash Univ, Dept Mat Sci & Engn, 22 Alliance Lane, Clayton, Vic 3800, Australia.
    Liu, Peng
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Zhang, Biaobiao
    KTH Royal Inst Technol, Dept Chem, Organ Chem, SE-10044 Stockholm, Sweden.
    Chen, Hong
    KTH Royal Inst Technol, Dept Chem, Organ Chem, SE-10044 Stockholm, Sweden.
    Inge, A. Ken
    Stockholm Univ, Dept Mat & Environm Chem MMK, SE-10691 Stockholm, Sweden.
    Li, Yuanyuan
    KTH Royal Inst Technol, Dept Fibre & Polymer Technol, Wallenberg Wood Sci Ctr, SE-10044 Stockholm, Sweden.
    Wang, Haoxin
    Dalian Univ Technol, Inst Artificial Photosynth, DUT KTH Joint Educ & Res Ctr Mol Devices, State Key Lab Fine Chem, Dalian 116024, Peoples R China.
    Cheng, Yi-Bing
    Monash Univ, Dept Mat Sci & Engn, 22 Alliance Lane, Clayton, Vic 3800, Australia.
    Kloo, Lars
    KTH Royal Inst Technol, Dept Chem, Ctr Mol Devices, Appl Phys Chem, SE-10044 Stockholm, Sweden.
    Sun, Licheng
    KTH Royal Inst Technol, Dept Chem, Organ Chem, SE-10044 Stockholm, Sweden;Dalian Univ Technol, Inst Artificial Photosynth, DUT KTH Joint Educ & Res Ctr Mol Devices, State Key Lab Fine Chem, Dalian 116024, Peoples R China.
    Design and synthesis of dopant-free organic hole-transport materials for perovskite solar cells2018In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, no 69, p. 9571-9574Article in journal (Refereed)
    Abstract [en]

    Two novel dopant-free hole-transport materials (HTMs) with spiro[dibenzo[c,h]xanthene-7,9-fluorene] (SDBXF) skeletons were prepared via facile synthesis routes. A power conversion efficiency of 15.9% in perovskite solar cells is attained by using one HTM without dopants, which is much higher than undoped Spiro-OMeTAD-based devices (10.8%). The crystal structures of both new HTMs were systematically investigated to reveal the reasons behind such differences in performance and to indicate the design principles of more advanced HTMs.

  • 11.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolutionary and Pharmacological Studies of NPY and QRFP Receptors2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The neuropeptide Y (NPY) system consists of 3-4 peptides and 4-7 receptors in vertebrates. It has powerful effects on appetite regulation and is involved in many other biological processes including blood pressure regulation, bone formation and anxiety. This thesis describes studies of the evolution of the NPY system by comparison of several vertebrate species and structural studies of the human Y2 receptor, which reduces appetite, to identify amino acid residues involved in peptide-receptor interactions.

    The NPY system was studied in zebrafish (Danio rerio), western clawed frog (Xenopus tropicalis), and sea lamprey (Petromyzon marinus). The receptors were cloned and functionally expressed and their pharmacological profiles were determined using the native peptides in either binding studies or a signal transduction assay. Some peptide-receptor preferences were observed, indicating functional specialization.

    A receptor family closely related to the NPY receptors, called the QRFP receptors, was investigated. A QRFP receptor was cloned from amphioxus, Branchistoma floridae, showing that the receptor arose before the origin of the vertebrates. Evolutionary studies demonstrated that the ancestral vertebrate had as many as four QRFP receptors, only one of which remains in mammals today. This correlates with the NPY receptor family, located in the same chromosomal regions, which had seven members in the ancestral vertebrate but only 4-5 in living mammals. Some vertebrates have considerably more complex NPY and QRFP receptor systems than humans and other mammals.

    Two studies investigated interactions of NPY-family peptides with the human Y2 receptor. Candidate residues, selected based on structural modeling and docking, were mutated to disrupt possible interactions with peptide ligands. The modified receptors were expressed in cultured cells and investigated by measuring binding and functional responses. Several receptor residues were found to influence peptide-receptor interactions, some of which are involved in maintaining receptor structure. In a pilot study, the kinetics of peptide-receptor interaction were found to be very slow, of the order several hours.

    In conclusion, this thesis clarifies evolutionary relationships for the complex NPY and QRFP peptide-receptor systems and improves the structural models of the human NPY-family receptors, especially Y2. These results will hopefully facilitate drug design for targeting of NPY-family receptors.

    List of papers
    1. Cloning and pharmacological characterization of the neuropeptide Y receptor Y5 in the sea lamprey, Petromyzon marinus
    Open this publication in new window or tab >>Cloning and pharmacological characterization of the neuropeptide Y receptor Y5 in the sea lamprey, Petromyzon marinus
    Show others...
    2013 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 39, p. 64-70Article in journal (Refereed) Published
    Abstract [en]

    The neuropeptide Y system is known to have expanded in early vertebrate evolution. Three neuropeptide Y receptors have been proposed to have existed before the two basal vertebrate tetraploidizations, namely a VI-like, a Y2-like, and a Y5-like receptor, with their genes in the same chromosomal region. Previously we have described a VI-subfamily and a Y2-subfamily receptor in the river lamprey, Lampetra fluviatilis. Here we report the identification of a Y5 receptor in the genome of the sea lamprey, Petromyzon marinus. In phylogenetic analyses, the Y5 receptor clusters together with gnathostome Y5 receptors with high bootstrap value and shares the long intracellular loop 3. This lamprey receptor has an even longer loop 3 than the gnathostome Y5 receptors described so far, with the expansion of amino acid repeats. Functional expression in a human cell line, co-transfected with a modified human G-protein, resulted in inositol phosphate turnover in response to the three lamprey NPY-family peptides NPY, PYY and PMY at nanomolar concentrations. Our results confirm that the Y1-Y2-Y5 receptor gene triplet arose before the cyclostome-gnathostome divergence. However, it is not clear from the NPY receptors whether cyclostomes diverged from the gnathostome lineage after the first or the second tetraploidization. Duplicates resulting from the tetraploidizations exist for both Y1 and Y2 in gnathostomes, but only a single copy of Y5 has survived in all vertebrates characterized to date, making the physiological roles of Y5 interesting to explore.

    Keywords
    Lamprey, Neuropeptide Y, Peptide YY, Y5 receptor
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-198074 (URN)10.1016/j.peptides.2012.11.007 (DOI)000315839300011 ()
    Available from: 2013-04-09 Created: 2013-04-08 Last updated: 2019-01-03Bibliographically approved
    2. Neuropeptide Y family receptors Y1 and Y2 from sea lamprey, Petromyzon marinus: cloning and pharmacological characterization
    Open this publication in new window or tab >>Neuropeptide Y family receptors Y1 and Y2 from sea lamprey, Petromyzon marinus: cloning and pharmacological characterization
    2015 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 222, p. 106-115Article in journal (Other academic) Published
    Abstract [en]

    The vertebrate gene family for neuropeptide Y (NPY) receptors expanded by duplication of the chromosome carrying the ancestral Y1–Y2–Y5 gene triplet. After loss of some duplicates, the ancestral jawed vertebrate had seven receptor subtypes forming the Y1 (including Y1, Y4, Y6, Y8), Y2 (including Y2, Y7) and Y5 (only Y5) subfamilies. Lampreys are considered to have experienced the same chromosome duplications as gnathostomes and should also be expected to have multiple receptor genes. However, previously only a Y4-like and a Y5 receptor have been cloned and characterized. Here we report the cloning and characterization of two additional receptors from the sea lamprey Petromyzon marinus. Sequence phylogeny alone could not with certainty assign their identity, but based on synteny comparisons of P. marinus and the Arctic lamprey, Lethenteron camtschaticum, with jawed vertebrates, the two receptors most likely are Y1 and Y2. Both receptors were expressed in human HEK293 cells and inositol phosphate assays were performed to determine the response to the three native lamprey peptides NPY, PYY and PMY. The three peptides have similar potencies in the nanomolar range for Y1. No obvious response to the three peptides was detected for Y2. Synteny analysis supports identification of the previously cloned receptor as Y4. No additional NPY receptor genes could be identified in the presently available lamprey genome assemblies. Thus, four NPY-family receptors have been identified in lampreys, orthologs of the same subtypes as in humans (Y1, Y2, Y4 and Y5), whereas many other vertebrate lineages have retained additional ancestral subtypes.

    National Category
    Evolutionary Biology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-233437 (URN)10.1016/j.ygcen.2015.08.005 (DOI)000366438000012 ()26255155 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2014-10-06 Created: 2014-10-05 Last updated: 2019-01-03Bibliographically approved
    3. Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes
    Open this publication in new window or tab >>Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes
    Show others...
    2012 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 177, no 3, p. 322-331Article in journal (Refereed) Published
    Abstract [en]

    Neuropeptide Y and its related peptides PYY and PP (pancreatic polypeptide) are involved in feeding behavior, regulation of the pituitary and the gastrointestinal tract, and numerous other functions. The peptides act on a family of G-protein coupled receptors with 4-7 members in jawed vertebrates. We describe here the NPY system of the Western clawed frog Silurana (Xenopus) tropicalis. Three peptides, NPY, PYY and PP, were identified together with six receptors, namely subtypes Y1, Y2, Y4, Y5, Y7 and Y8. Thus, this frog has all but one of the ancestral seven gnathostome NPY-family receptors, in contrast to mammals which have lost 2-3 of the receptors. Expression levels of mRNA for the peptide and receptor genes were analyzed in a panel of 19 frog tissues using reverse transcriptase quantitative PCR. The peptide mRNAs had broad distribution with highest expression in skin, blood and small intestine. NPY mRNA was present in the three brain regions investigated, but PYY and PP mRNAs were not detectable in any of these. All receptor mRNAs had similar expression profiles with high expression in skin, blood, muscle and heart. Three of the receptors, Y5, Y7 and Y8, could be functionally expressed in HEK-293 cells and characterized with binding studies using the three frog peptides. PYY had the highest affinity for all three receptors (K(i) 0.042-0.34 nM). Also NPY and PP bound to the Y8 receptor with high affinity (0.14 and 0.50 nM). The low affinity of NPY for the Y5 receptor (100-fold lower than PYY) differs from mammals and chicken. This may suggest a less important role of NPY on Y5 in appetite stimulation in the frog compared with amniotes. In conclusion, our characterization of the NPY system in S. tropicalis with its six receptors demonstrates not only greater complexity than in mammals but also some interesting differences in ligand-receptor preferences.

    Keywords
    NPY, PYY, G-protein-coupled receptor, Silurana tropicalis, evolution
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-129517 (URN)10.1016/j.ygcen.2012.04.027 (DOI)000306390100005 ()22565163 (PubMedID)
    Note

    Erratum in General and Comparative Endocrinology 2015:215, doi:10.1016/j.ygcen.2014.11.014.

    Available from: 2010-08-18 Created: 2010-08-18 Last updated: 2019-01-03Bibliographically approved
    4. Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b
    Open this publication in new window or tab >>Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b
    Show others...
    2013 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 7, article id 29Article in journal (Refereed) Published
    Abstract [en]

    The neuropeptide Y (NPY) system influences numerous physiological functions including feeding behavior, endocrine regulation, and cardiovascular regulation. In jawed vertebrates it consists of 3-4 peptides and 4-7 receptors. Teleost fishes have unique duplicates of NPY and PYY as well as the Y8 receptor. In the zebrafish, the NPY system consists of the peptides NPYa, PYYa, and PYYb (NPYb appears to have been lost) and at least seven NPY receptors: Y1, Y2, Y2-2, Y4, Y7, Y8a, and Y8b. Previously PYYb binding has been reported for Y2 and Y2-2. To search for peptide-receptor preferences, we have investigated PYYb binding to four of the remaining receptors and compared with NPYa and PYYa. Taken together, the most striking observations are that PYYa displays reduced affinity for Y2 (3 nM) compared to the other peptides and receptors and that all three peptides have higher affinity for Y4 (0.028-0.034 nM) than for the other five receptors. The strongest peptide preference by any receptor selectivity is the one previously reported for PYYb by the Y2 receptor, as compared to NPY and PYYa. These affinity differences may be helpful to elucidate specific details of peptide-receptor interactions. Also, we have investigated the level of mRNA expression in different organs using qPCR. All peptides and receptors have higher expression in heart, kidney, and brain. These quantitative aspects on receptor affinities and mRNA distribution help provide a more complete picture of the NPY system.

    Keywords
    Evolution, genome duplication, NPY, elephant shark
    National Category
    Natural Sciences Neurology
    Research subject
    Neuroscience
    Identifiers
    urn:nbn:se:uu:diva-205599 (URN)10.3389/fnins.2013.00029 (DOI)000346567300029 ()23508731 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2013-08-20 Created: 2013-08-20 Last updated: 2019-01-03Bibliographically approved
    5. Characterization of peptide QRFP (26RFa) and its receptor from amphioxus, Branchiostoma floridae
    Open this publication in new window or tab >>Characterization of peptide QRFP (26RFa) and its receptor from amphioxus, Branchiostoma floridae
    Show others...
    2015 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 210, p. 107-113Article in journal (Refereed) Published
    Abstract [en]

    A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3μM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.

    Keywords
    Neuropeptide, receptor, evolution
    National Category
    Neurosciences
    Research subject
    Evolutionary Genetics; Neuroscience
    Identifiers
    urn:nbn:se:uu:diva-240039 (URN)10.1016/j.ygcen.2014.10.010 (DOI)000346886400012 ()25449662 (PubMedID)
    Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2019-01-03Bibliographically approved
    6. Unexpected multiplicity of QRFP receptors in early vertebrate evolution
    Open this publication in new window or tab >>Unexpected multiplicity of QRFP receptors in early vertebrate evolution
    2014 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, p. 337-Article in journal (Refereed) Published
    Abstract [en]

    The neuropeptide QRFP, also called 26RFa, and its G protein-coupled receptor GPR103 have been identified in all vertebrates investigated. In mammals, this peptide-receptor pair has been found to have several effects including stimulation of appetite. Recently, we reported that a QRFP peptide is present in amphioxus, Branchiostoma floridae, and we also identified a QRFP receptor (QRFPR) that mediates a functional response to sub-nanomolar concentrations of the amphioxus peptide as well as short and long human QRFP (Xu et al., submitted). Because the ancestral vertebrate underwent two tetraploidizations, it might be expected that duplicates of the QRFP gene and its receptor gene may exist. Indeed, we report here the identification of multiple vertebrate QRFPR genes. Three QRFPR genes are present in the coelacanth Latimeria chalumnae, representing an early diverging sarcopterygian lineage. Three QRFPR genes are present in the basal actinopterygian fish, the spotted gar. Phylogenetic and chromosomal analyses show that only two of these receptor genes are orthologous between the two species, thus demonstrating a total of four distinct vertebrate genes. Three of the QRFPR genes resulted from the early vertebrate tetraploidizations and were copied along with syntenic neuropeptide Y receptor genes. The fourth QRFPR gene may be an even older and distinct lineage. Because mammals and birds have only a single QRFPR gene, this means that three genes have been lost in these lineages, and at least one of these was lost independently in mammals and birds because it is still present in a turtle. In conclusion, these results show that the QRFP system gained considerable complexity in the early stages of vertebrate evolution and still maintains much of this in some lineages, and that it has been secondarily reduced in mammals.

    Keywords
    Neuropeptide, receptor, evolution
    National Category
    Natural Sciences
    Research subject
    Neuroscience; Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-240037 (URN)10.3389/fnins.2014.00337 (DOI)000346532900001 ()25386115 (PubMedID)
    Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2019-01-03Bibliographically approved
    7. Mutagenesis and Computational Modeling of Human G‑Protein-Coupled Receptor Y2 for Neuropeptide Y and Peptide YY
    Open this publication in new window or tab >>Mutagenesis and Computational Modeling of Human G‑Protein-Coupled Receptor Y2 for Neuropeptide Y and Peptide YY
    Show others...
    2013 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 52, no 45, p. 7987-7998Article in journal (Refereed) Published
    Abstract [en]

    Neuropeptide Y and peptide YY receptor type 2 (Y2) is involved in appetite regulation and several other physiological processes. We have investigated the structure of the human Y2 receptor. Computational modeling of receptor–agonist interactions was used as a guide to design a series of receptor mutants, followed by binding assays using full-length and truncated peptide agonists and the Y2-specific antagonist BIIE0246. Our model suggested a hydrogen bond network among highly conserved residues Thr2.61, Gln3.32, and His7.39, which could play roles in ligand binding and/or receptor structure. In addition, the C-terminus of the peptide could make contact with residues Tyr5.38 and Leu6.51. Mutagenesis of all these positions, followed by binding assays, provides experimental support for our computational model: most of the mutants for the residues forming the proposed hydrogen bond network displayed reduced peptide agonist affinities as well as reduced hPYY3-36 potency in a functional assay. The Ala and Leu mutants of Gln3.32 and His7.39 disrupted membrane expression of the receptor. Combined with the modeling, the experimental results support roles for these hydrogen bond network residues in peptide binding as well as receptor architecture. The reduced agonist affinity for mutants of Tyr5.38 and Leu6.51 supports their role in a binding pocket surrounding the invariant tyrosine at position 36 of the peptide ligands. The results for antagonist BIIE0246 suggest several differences in interactions compared to those of the peptides. Our results lead to a new structural model for NPY family receptors and peptide binding.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2013
    National Category
    Natural Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-154994 (URN)10.1021/bi400830c (DOI)000330017700012 ()
    Available from: 2011-08-04 Created: 2011-06-14 Last updated: 2019-01-03Bibliographically approved
    8. Detecting ligand interactions with G protein-coupled receptors in real-time on living cells
    Open this publication in new window or tab >>Detecting ligand interactions with G protein-coupled receptors in real-time on living cells
    Show others...
    2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, p. 820-824Article in journal (Refereed) Published
    Abstract [en]

    G protein-coupled receptors (GPCRs) are a large group of receptors of great biological and clinical relevance. Despite this, the tools for a detailed analysis of ligand-GPCR interactions are limited. The aim of this paper was to demonstrate how ligand binding to GPCRs can be followed in real-time on living cells. This was conducted using two model systems, the radiolabeled porcine peptide YY (pPYY) interacting with transfected human Y2 receptor (hY2R) and the bombesin antagonist RM26 binding to the naturally expressed gastrin-releasing peptide receptor (GRPR). By following the interaction over time, the affinity and kinetic properties such as association and dissociation rate were obtained. Additionally, data were analyzed using the Interaction Map method, which can evaluate a real-time binding curve and present the number of parallel interactions contributing to the curve. It was found that pPYY binds very slowly with an estimated time to equilibrium of approximately 12 h. This may be problematic in standard end-point assays where equilibrium is required. The RM26 binding showed signs of heterogeneity, observed as two parallel interactions with unique kinetic properties. In conclusion, measuring binding in real-time using living cells opens up for a better understanding of ligand interactions with GPCRs.

    Keywords
    GPCR, Real-time, LigandTracer, Interaction Map, Kinetics, Heterogeneity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-215943 (URN)10.1016/j.bbrc.2013.10.149 (DOI)000328434800022 ()
    Note

    De två första författarna delar första författarskapet.

    Available from: 2014-01-17 Created: 2014-01-17 Last updated: 2019-01-03Bibliographically approved
  • 12.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Fällmar, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Boukharta, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Pruner, Jasna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Gutiérrez-de-Terán, Hugo
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mutagenesis and Computational Modeling of Human G‑Protein-Coupled Receptor Y2 for Neuropeptide Y and Peptide YY2013In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 52, no 45, p. 7987-7998Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y and peptide YY receptor type 2 (Y2) is involved in appetite regulation and several other physiological processes. We have investigated the structure of the human Y2 receptor. Computational modeling of receptor–agonist interactions was used as a guide to design a series of receptor mutants, followed by binding assays using full-length and truncated peptide agonists and the Y2-specific antagonist BIIE0246. Our model suggested a hydrogen bond network among highly conserved residues Thr2.61, Gln3.32, and His7.39, which could play roles in ligand binding and/or receptor structure. In addition, the C-terminus of the peptide could make contact with residues Tyr5.38 and Leu6.51. Mutagenesis of all these positions, followed by binding assays, provides experimental support for our computational model: most of the mutants for the residues forming the proposed hydrogen bond network displayed reduced peptide agonist affinities as well as reduced hPYY3-36 potency in a functional assay. The Ala and Leu mutants of Gln3.32 and His7.39 disrupted membrane expression of the receptor. Combined with the modeling, the experimental results support roles for these hydrogen bond network residues in peptide binding as well as receptor architecture. The reduced agonist affinity for mutants of Tyr5.38 and Leu6.51 supports their role in a binding pocket surrounding the invariant tyrosine at position 36 of the peptide ligands. The results for antagonist BIIE0246 suggest several differences in interactions compared to those of the peptides. Our results lead to a new structural model for NPY family receptors and peptide binding.

  • 13.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lagman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Görel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Neuropeptide Y family receptors Y1 and Y2 from sea lamprey, Petromyzon marinus: cloning and pharmacological characterization2015In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 222, p. 106-115Article in journal (Other academic)
    Abstract [en]

    The vertebrate gene family for neuropeptide Y (NPY) receptors expanded by duplication of the chromosome carrying the ancestral Y1–Y2–Y5 gene triplet. After loss of some duplicates, the ancestral jawed vertebrate had seven receptor subtypes forming the Y1 (including Y1, Y4, Y6, Y8), Y2 (including Y2, Y7) and Y5 (only Y5) subfamilies. Lampreys are considered to have experienced the same chromosome duplications as gnathostomes and should also be expected to have multiple receptor genes. However, previously only a Y4-like and a Y5 receptor have been cloned and characterized. Here we report the cloning and characterization of two additional receptors from the sea lamprey Petromyzon marinus. Sequence phylogeny alone could not with certainty assign their identity, but based on synteny comparisons of P. marinus and the Arctic lamprey, Lethenteron camtschaticum, with jawed vertebrates, the two receptors most likely are Y1 and Y2. Both receptors were expressed in human HEK293 cells and inositol phosphate assays were performed to determine the response to the three native lamprey peptides NPY, PYY and PMY. The three peptides have similar potencies in the nanomolar range for Y1. No obvious response to the three peptides was detected for Y2. Synteny analysis supports identification of the previously cloned receptor as Y4. No additional NPY receptor genes could be identified in the presently available lamprey genome assemblies. Thus, four NPY-family receptors have been identified in lampreys, orthologs of the same subtypes as in humans (Y1, Y2, Y4 and Y5), whereas many other vertebrate lineages have retained additional ancestral subtypes.

  • 14.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Kuraku, Shigehiro
    RIKEN Center for Developmental Biology.
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Cloning and pharmacological characterization of the neuropeptide Y receptor Y5 in the sea lamprey, Petromyzon marinus2013In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 39, p. 64-70Article in journal (Refereed)
    Abstract [en]

    The neuropeptide Y system is known to have expanded in early vertebrate evolution. Three neuropeptide Y receptors have been proposed to have existed before the two basal vertebrate tetraploidizations, namely a VI-like, a Y2-like, and a Y5-like receptor, with their genes in the same chromosomal region. Previously we have described a VI-subfamily and a Y2-subfamily receptor in the river lamprey, Lampetra fluviatilis. Here we report the identification of a Y5 receptor in the genome of the sea lamprey, Petromyzon marinus. In phylogenetic analyses, the Y5 receptor clusters together with gnathostome Y5 receptors with high bootstrap value and shares the long intracellular loop 3. This lamprey receptor has an even longer loop 3 than the gnathostome Y5 receptors described so far, with the expansion of amino acid repeats. Functional expression in a human cell line, co-transfected with a modified human G-protein, resulted in inositol phosphate turnover in response to the three lamprey NPY-family peptides NPY, PYY and PMY at nanomolar concentrations. Our results confirm that the Y1-Y2-Y5 receptor gene triplet arose before the cyclostome-gnathostome divergence. However, it is not clear from the NPY receptors whether cyclostomes diverged from the gnathostome lineage after the first or the second tetraploidization. Duplicates resulting from the tetraploidizations exist for both Y1 and Y2 in gnathostomes, but only a single copy of Y5 has survived in all vertebrates characterized to date, making the physiological roles of Y5 interesting to explore.

  • 15.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Tian, Lei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Etman, Ahmed S.
    Stockholm Univ, Dept Mat & Environm Chem, Svante Arrhenius Vag 16C, SE-10691 Stockholm, Sweden.
    Sun, Junliang
    Stockholm Univ, Dept Mat & Environm Chem, Svante Arrhenius Vag 16C, SE-10691 Stockholm, Sweden;Peking Univ, Beijing Natl Lab Mol Sci, Coll Chem & Mol Engn, Beijing 100871, Peoples R China.
    Tian, Haining
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Solution-processed nanoporous NiO-dye-ZnO photocathodes: Toward efficient and stable solid-state p-type dye-sensitized solar cells and dye-sensitized photoelectrosynthesis cells2019In: Nano Energy, ISSN 2211-2855, E-ISSN 2211-3282, Vol. 55, p. 59-64Article in journal (Refereed)
    Abstract [en]

    A solution-processed NiO-dye-ZnO photocathode was developed for applications in both solid-state p-type dye-sensitized solar cells (p-ssDSCs) and p-type dye-sensitized photoelectrosynthesis cells (p-DSPECs). In p-ssDSCs, the solar cell using ZnO as electron transport material showed a short circuit current, up to 680 mu A cm(-2), which is 60-fold larger than that previously reported device using TiO2 as electron transport material with similar architecture. In the p-DSPECs, a remarkable photocurrent of 100 mu A cm(-2) was achieved in a pH = 5.0 acetate buffer solution under a bias potential at 0.05 V vs RHE with platinum as the proton reduction catalyst. A Faradaic efficiency approaching 100% for the H-2 evolution reaction was obtained after photoelectrolysis for 9 h. Importantly, the solution-processed NiO-dye-ZnO photocathode exhibited excellent long-term stability in both p-ssDSCs and p-DSPECs. To the best of our knowledge, this is the first study where a solution-processable, nanoporous NiO-dye-ZnO photocathode is used for both p-ssDSCs and p-DSPECs having both excellent device performance and stability.

  • 16.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Björkelund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Detecting ligand interactions with G protein-coupled receptors in real-time on living cells2013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, p. 820-824Article in journal (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) are a large group of receptors of great biological and clinical relevance. Despite this, the tools for a detailed analysis of ligand-GPCR interactions are limited. The aim of this paper was to demonstrate how ligand binding to GPCRs can be followed in real-time on living cells. This was conducted using two model systems, the radiolabeled porcine peptide YY (pPYY) interacting with transfected human Y2 receptor (hY2R) and the bombesin antagonist RM26 binding to the naturally expressed gastrin-releasing peptide receptor (GRPR). By following the interaction over time, the affinity and kinetic properties such as association and dissociation rate were obtained. Additionally, data were analyzed using the Interaction Map method, which can evaluate a real-time binding curve and present the number of parallel interactions contributing to the curve. It was found that pPYY binds very slowly with an estimated time to equilibrium of approximately 12 h. This may be problematic in standard end-point assays where equilibrium is required. The RM26 binding showed signs of heterogeneity, observed as two parallel interactions with unique kinetic properties. In conclusion, measuring binding in real-time using living cells opens up for a better understanding of ligand interactions with GPCRs.

  • 17.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Vasile, Silvana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Østergaard, Søren
    Novo Nordisk AS, Prot & Peptide Chem 2, Malov, Denmark.
    Paulsson, Johan F.
    Novo Nordisk AS, Obes Res, Malov, Denmark.
    Pruner, Jasna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Wulff, Birgitte S.
    Novo Nordisk AS, Obes Res, Malov, Denmark.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Elucidation of the Binding Mode of the Carboxyterminal Region of Peptide YY to the Human Y-2 Receptor2018In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 93, no 4, p. 323-334Article in journal (Refereed)
    Abstract [en]

    Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here the results of a multidisciplinary approach to elucidate the binding mode of the native peptide agonist PYY to the human Y2 receptor, based on computational modeling, peptide chemistry and in vitro pharmacological analyses. The preserved binding orientation proposed for full-length PYY and five analogs, truncated at the amino terminus, explains our pharmacological results where truncations of the N-terminal proline helix showed little effect on peptide affinity. This was followed by receptor mutagenesis to investigate the roles of several receptor positions suggested by the modeling. As a complement, PYY-(3-36) analogs were synthesized with modifications at different positions in the common PYY/NPY C-terminal fragment (32TRQRY36-amide). The results were assessed and interpreted by molecular dynamics and Free Energy Perturbation (FEP) simulations of selected mutants, providing a detailed map of the interactions of the PYY/NPY C-terminal fragment with the transmembrane cavity of the Y2 receptor. The amidated C-terminus would be stabilized by polar interactions with Gln2886.55 and Tyr2195.39, while Gln1303.32 contributes to interactions with Q34 in the peptide and T32 is close to the tip of TM7 in the receptor. This leaves the core, α-helix of the peptide exposed to make potential interactions with the extracellular loops. This model agrees with most experimental data available for the Y2 system and can be used as a basis for optimization of Y2 receptor agonists.

  • 18.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Wrede, Sina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Curtze, Allison
    Ohio State Univ, Dept Chem & Biochem, 100 West 18th Ave, Columbus, OH 43210 USA.
    Tian, Lei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Pati, Palas Baran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Kloo, Lars
    KTH Royal Inst Technol, Dept Chem, Appl Phys Chem, S-10044 Stockholm, Sweden.
    Wu, Yiying
    Ohio State Univ, Dept Chem & Biochem, 100 West 18th Ave, Columbus, OH 43210 USA.
    Tian, Haining
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    An Indacenodithieno[3,2-b]thiophene-Based Organic Dye for Solid-State p-Type Dye-Sensitized Solar Cells2019In: ChemSusChem, ISSN 1864-5631, E-ISSN 1864-564X, Vol. 12, no 14, p. 3243-3248Article in journal (Refereed)
    Abstract [en]

    An indacenodithieno[3,2-b]thiophene (IDTT) unit is used as a linker moiety to design a new p-type dye-TIP-for solid-state p-type dye-sensitized solar cells. Solar cells based on the TIP dye offered an efficiency of 0.18 % with an open-circuit photovoltage of 550 mV and a short-circuit photocurrent density of 0.86 mA cm(-2), which is better than those of two reference dyes, PB6 and BH4. Charge lifetime experiments reveal that the IDTT linker-based TIP dye significantly suppresses charge recombination losses in the devices.

  • 19.
    Xu, Peng
    et al.
    Yunnan Univ, Sch Mat Sci & Engn, Yunnan Key Lab Micro Nano Mat & Technol, Kunming 650091, Yunnan, Peoples R China.
    Liu, Peng
    KTH Royal Inst Technol, Appl Phys Chem, Dept Chem, Teknikringen 30, SE-10044 Stockholm, Sweden.
    Li, Yuanyuan
    KTH Royal Inst Technol, Wallenberg Wood Sci Ctr, Dept Fiber & Polymer Technol, Chem Sci & Engn, SE-10044 Stockholm, Sweden.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Kloo, Lars
    KTH Royal Inst Technol, Appl Phys Chem, Dept Chem, Teknikringen 30, SE-10044 Stockholm, Sweden.
    Sun, Licheng
    KTH Royal Inst Technol, Organ Chem, Dept Chem, SE-10044 Stockholm, Sweden.
    Hua, Yong
    Yunnan Univ, Sch Mat Sci & Engn, Yunnan Key Lab Micro Nano Mat & Technol, Kunming 650091, Yunnan, Peoples R China.
    D-A-D-Typed Hole Transport Materials for Efficient Perovskite Solar Cells: Tuning Photovoltaic Properties via the Acceptor Group2018In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 10, no 23, p. 19697-19703Article in journal (Refereed)
    Abstract [en]

    Two D-A-D-structured hole-transport materials (YN1 and YN2) have been synthesized and used in perovskite solar cells. The two HTMs have low-lying HOMO levels and impressive mobility. Perovskite-based solar cells (PSCs) fabricated with YN2 showed a power conversion efficiency (PCE) value of 19.27% in ambient air, which is significantly higher than that of Spiro-OMeTAD (17.80%). PSCs based on YN1 showed an inferior PCE of 16.03%. We found that the incorporation of the stronger electron-withdrawing group in the HTM YN2 improves the PCE of PSCs. Furthermore, the YN2-based PSCs exhibit good long-term stability retaining 91.3% of its initial efficiency, whereas PSCs based on Spiro-OMeTAD retained only 42.2% after 1000 h lifetime (dark conditions). These promising results can provide a new strategy for the design of D-A-D HTMs for PSC applications in future.

  • 20.
    Yang, Zhenlin
    et al.
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China.
    Han, Shuo
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China.
    Keller, Max
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Kaiser, Anette
    Bender, Brian J.
    Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA.
    Bosse, Mathias
    Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany.
    Burkert, Kerstin
    Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany.
    Koegler, Lisa M.
    Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany.
    Wifling, David
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Bernhardt, Guenther
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Plank, Nicole
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Littmann, Timo
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Schmidt, Peter
    Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany.
    Yi, Cuiying
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China.
    Li, Beibei
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China.
    Ye, Sheng
    Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China.
    Zhang, Rongguang
    Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China;Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai, Peoples R China.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stevens, Raymond C.
    ShanghaiTech Univ, Human Inst, Shanghai, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China.
    Huster, Daniel
    Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany.
    Meiler, Jens
    Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA;Vanderbilt Univ, Struct Biol Ctr, Dept Chem, 221 Kirkland Hall, Nashville, TN 37235 USA;Vanderbilt Univ, Dept Bioinformat, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA.
    Zhao, Qiang
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China.
    Beck-Sickinger, Annette G.
    Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany.
    Buschauer, Armin
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Wu, Beili
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China.
    Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 556, no 7702, p. 520-524Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology(1,2). The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y-1, Y-2, Y-4 and Y-5 receptors, with different affinity and selectivity(3). NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y-1 receptor (Y1R)(4). A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity(4), tumour(1) and bone loss(5). However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability(6). Here we report crystal structures of the human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 angstrom resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y1R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery that targets NPY receptors.

  • 21.
    Zhang, Jinbao
    et al.
    Monash Univ, Dept Mat Sci & Engn, Clayton, Vic 3800, Australia.
    Daniel, Quentin
    KTH Royal Inst Technol, Organ Chem, Ctr Mol Devices, Dept Chem Chem Sci & Engn, SE-10044 Stockholm, Sweden.
    Zhang, Tian
    Monash Univ, Dept Mat Sci & Engn, Clayton, Vic 3800, Australia.
    Wen, Xiaoming
    Swinburne Univ Technol, Ctr Microphoton, Melbourne, Vic 3122, Australia.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Sun, Licheng
    KTH Royal Inst Technol, Organ Chem, Ctr Mol Devices, Dept Chem Chem Sci & Engn, SE-10044 Stockholm, Sweden;Dalian Univ Technol, State Key Lab Fine Chem, DUT KTH Joint Educ & Res Ctr Mol Devices, Dalian 116012, Peoples R China.
    Bach, Udo
    Monash Univ, Dept Chem Engn, Clayton, Vic 3800, Australia;CSIRO Mfg, Clayton, Vic 3168, Australia;Melbourne Ctr Nanofabricat, Clayton, Vic 3800, Australia.
    Cheng, Yi-Bing
    Monash Univ, Dept Mat Sci & Engn, Clayton, Vic 3800, Australia;Wuhan Univ Technol, State Key Lab Silicate Mat Architectures, Wuhan 430070, Hubei, Peoples R China.
    Chemical Dopant Engineering in Hole Transport Layers for Efficient Perovskite Solar Cells: Insight into the Interfacial Recombination2018In: ACS Nano, ISSN 1936-0851, E-ISSN 1936-086X, Vol. 12, no 10, p. 10452-10462Article in journal (Refereed)
    Abstract [en]

    Chemical doping of organic semiconductors has been recognized as an effective way to enhance the electrical conductivity. In perovskite solar cells (PSCs), various types of dopants have been developed for organic hole transport materials (HTMs); however, the knowledge of the basic requirements for being efficient dopants as well as the comprehensive roles of the dopants in PSCs has not been clearly revealed. Here, three copper-based complexes with controlled redox activities are applied as dopants in PSCs, and it is found that the oxidative reactivity of dopants presents substantial impacts on conductivity, charge dynamics, and solar cell performance. A significant improvement of open- circuit voltage (V-oc) by more than 100 mV and an increase of power conversion efficiency from 13.2 to 19.3% have been achieved by tuning the doping level of the HTM. The observed large variation of V-oc for three dopants reveals their different recombination kinetics at the perovskite/HTM interfaces and suggests a model of an interfacial recombination mechanism. We also suggest that the dopants in HTMs can also affect the charge recombination kinetics as well as the solar cell performance. Based on these findings, a strategy is proposed to physically passivate the electron- hole recombination by inserting an ultrathin Al2O3 insulating layer between the perovskite and the HTM. This strategy contributes a significant enhancement of the power conversion efficiency and environmental stability, indicating that dopant engineering is one crucial way to further improve the performance of PSCs.

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