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High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
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2003 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 51, 51521-51526 p.Article in journal (Refereed) Published
Abstract [en]

We created a molecular model of the human melanocortin 4 receptor (MC4R) and introduced a series of His residues into the receptor protein to form metal ion binding sites. We were able to insert micromolar affinity binding sites for zinc between transmembrane region (TM) 2 and TM3 where the metal ion alone was able to activate this peptide binding G-protein-coupled receptor. The exact conformation of the metal ion interactions allowed us to predict the orientation of the helices, and remodeling of the receptor protein indicated that Glu100 and Ile104 in TM2 and Asp122 and Ile125 in TM3 are directed toward a putative area of activation of the receptor. The molecular model suggests that a rotation of TM3 may be important for activation of the MC4R. Previous models of G-protein-coupled receptors have suggested that unlocking of a stabilizing interaction between the DRY motif, in the cytosolic part of TM3, and TM6 is important for the activation process. We suggest that this unlocking process may be facilitated through creation of a new interaction between TM3 and TM2 in the MC4R.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2003. Vol. 278, no 51, 51521-51526 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94033DOI: 10.1074/jbc.M307683200ISI: 000187206300083PubMedID: 14523020OAI: oai:DiVA.org:uu-94033DiVA: diva2:167724
Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Classification, Evolution, Pharmacology and Structure of G protein-coupled Receptors
Open this publication in new window or tab >>Classification, Evolution, Pharmacology and Structure of G protein-coupled Receptors
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

G protein-coupled receptors (GPCR) are integral membrane proteins with seven α-helices that translate a remarkable diversity of signals into cellular responses. The superfamily of GPCRs is among the largest and most diverse protein families in vertebrates.

We have searched the human genome for GPCRs and show that the family includes approximately 800 proteins, which can divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin. This study represents one of the first overall road maps of the GPCR family in a mammalian genome. Moreover, we identified eight novel members of the human Adhesion family which are characterized by long N-termini with various domains. We also investigated the GPCR repertoire of the chicken genome, where we manually verified a total of 557 chicken GPCRs. We detected several specific expansions and deletions that may reflect some of the functional differences between human and chicken.

Substantial effort has been made over the years to find compounds that can bind and activate the melanocortin 4 receptor (MC4R). This receptor is involved in food intake and is thus an important target for antiobesity drugs. We used site-directed mutagenesis to insert micromolar affinity binding sites for zinc between transmembrane (TM) regions 2 and 3. We generated a molecular model of the human MC4R which suggests that a rotation of TM3 is important for activation of the MC4R.

Furthermore, we present seven new vertebrate prolactin releasing hormone receptors (PRLHRs) and show that they form two separate subtypes, PRLHR1 and PRLHR2. We performed a pharmacological characterization of the human PRLHR which showed that the receptor can bind neuropeptide Y (NPY) related ligands. We propose that an ancestral PRLH peptide has coevolved with a redundant NPY binding receptor, which then became PRLHR. This suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 108
Keyword
Pharmacology, Classification, Structure, Pharmacology, Evolution, G protein-coupled receptor, Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-6356 (URN)91-554-6466-1 (ISBN)
Public defence
2006-03-24, Room B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2013-04-04Bibliographically approved

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Lagerström, Malin C.Fredriksson, RobertHaitina, TatjanaLing, Maria K.Schiöth, Helgi B.

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