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  • 201.
    Wu, Xiongyu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Öhrngren, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Joshi, Advait A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Trejos, Alejandro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Persson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Arvela, Riina K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wallberg, Hans
    Medivir AB.
    Vrang, Lotta
    Medivir AB.
    Rosenquist, Åsa
    Medivir.
    Samuelsson, Bertil
    Medivir AB.
    Unge, Johan
    Lund University, MAX IV-laboratory .
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors2012Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 6, s. 2724-2736Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

  • 202.
    Zhang, Jingji
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Accuracy of mRNA Translation in Bacterial Protein Synthesis2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Reading of messenger RNA (mRNA) by aminoacyl-tRNAs (aa-tRNAs) on the ribosomes in the bacterial cell occurs with high accuracy. It follows from the physical chemistry of enzymatic reactions that there must be a trade-off between rate and accuracy of initial tRNA selection in protein synthesis: when the current accuracy, the A-value, approaches its maximal possible value, the d-value, the kinetic efficiency of the reaction approaches zero. We have used an in vitro system for mRNA translation with purified E. coli components to estimate the d- and A-values by which aa-tRNAs discriminate between their cognate and near cognate codons displayed in the ribosomal A site. In the case of tRNALys, we verified the prediction of a linear trade-off between kinetic efficiency of cognate codon reading and the accuracy of codon selection. These experiments have been extended to a larger set of tRNAs, including tRNAPhe, tRNAGlu, tRNAHis, tRNACys, tRNAAsp and tRNATyr, and linear efficiency-accuracy trade-off was observed in all cases. Similar to tRNALys, tRNAPhe discriminated with higher accuracy against a particular mismatch in the second than in the first codon position. Remarkably high d-values were observed for tRNAGlu discrimination against a C-C mismatch in the first codon position (70 000) and for tRNAPhe discrimination against an A-G mismatch in the second codon position (79 000). At the same time, we have found a remarkably small d-value (200) for tRNAGlu misreading G in the middle position of the codon (U-G mismatch).

    Aminoglycoside antibiotics induce large codon reading errors by tRNAs. We have studied the mechanism of aminoglycoside action and found that the drug stabilized aminoacyl-tRNA in a codon selective in relation to a codon non-selective state. This greatly enhanced the probability of near cognate aminoacyl-tRNAs to successfully transcend the initial selection step of the translating ribosome. We showed that Mg2+ ions, in contrast, favour codon non-selective states and thus induce errors in a principally different way than aminoglycosides. 

    We also designed experiments to estimate the overall accuracy of peptide bond formation with, including initial selection accuracy and proofreading of tRNAs after GTP hydrolysis on EF-Tu. Our experiments have now made it possible to calibrate the accuracy of tRNA selection in the test tube to that in the living cells. We will now also be able to investigate the degree to which the accuracy of tRNA selection has been optimized for maximal fitness.  

    Delarbeid
    1. Genetic code translation displays a linear trade-off between efficiency and accuracy of tRNA selection
    Åpne denne publikasjonen i ny fane eller vindu >>Genetic code translation displays a linear trade-off between efficiency and accuracy of tRNA selection
    2012 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 1, s. 131-136Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Rapid and accurate translation of the genetic code into protein is fundamental to life. Yet due to lack of a suitable assay, little is known about the accuracy-determining parameters and their correlation with translational speed. Here, we develop such an assay, based on Mg(2+) concentration changes, to determine maximal accuracy limits for a complete set of single-mismatch codon-anticodon interactions. We found a simple, linear trade-off between efficiency of cognate codon reading and accuracy of tRNA selection. The maximal accuracy was highest for the second codon position and lowest for the third. The results rationalize the existence of proofreading in code reading and have implications for the understanding of tRNA modifications, as well as of translation error-modulating ribosomal mutations and antibiotics. Finally, the results bridge the gap between in vivo and in vitro translation and allow us to calibrate our test tube conditions to represent the environment inside the living cell.

    Emneord
    fidelity, rate-accuracy trade-off, ribosome, protein synthesis, elongation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-167161 (URN)10.1073/pnas.1116480109 (DOI)000298876500031 ()
    Tilgjengelig fra: 2012-01-31 Laget: 2012-01-23 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    2. Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome
    Åpne denne publikasjonen i ny fane eller vindu >>Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome
    2015 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 31, s. 9602-9607Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We used a cell-free system with pure Escherichia coli components to study initial codon selection of aminoacyl-tRNAs in ternary complex with elongation factor Tu and GTP on messenger RNA-programmed ribosomes. We took advantage of the universal rate-accuracy trade-off for all enzymatic selections to determine how the efficiency of initial codon readings decreased linearly toward zero as the accuracy of discrimination against near-cognate and wobble codon readings increased toward the maximal asymptote, the d value. We report data on the rate-accuracy variation for 7 cognate, 7 wobble, and 56 near-cognate codon readings comprising about 15% of the genetic code. Their d values varied about 400-fold in the 200-80,000 range depending on type of mismatch, mismatch position in the codon, and tRNA isoacceptor type. We identified error hot spots (d = 200) for U:G misreading in second and U:U or G:A misreading in third codon position by His-tRNA(His) and, as also seen in vivo, Glu-tRNA(Glu). We suggest that the proofreading mechanism has evolved to attenuate error hot spots in initial selection such as those found here.

    Emneord
    protein synthesis, genetic code, misreading, error hot spots, kinetics
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261240 (URN)10.1073/pnas.1506823112 (DOI)000358930600052 ()26195797 (PubMedID)
    Forskningsfinansiär
    Swedish Research CouncilKnut and Alice Wallenberg Foundation
    Tilgjengelig fra: 2015-09-07 Laget: 2015-08-31 Sist oppdatert: 2017-12-04bibliografisk kontrollert
    3. Enhanced proofreading attenuates initial selection error hot spots in genetic code translation by transfer RNAs
    Åpne denne publikasjonen i ny fane eller vindu >>Enhanced proofreading attenuates initial selection error hot spots in genetic code translation by transfer RNAs
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    A system for cell free protein synthesis with E. coli components of high purity was used in conjunction with fast kinetics quench-flow measurements to characterize the accuracy of peptie bond formation by ribosomes with initiator tRNAfMet in P site and different codons in the A site. We used Glu-tRNAGlu, Lys-tRNALys and Phe-tRNAPhe in ternary complexes with EF-Tu and GTP to select ribosomes programmed with their respective cognate codons in competition with ribosomes containing near-cognate codons. Variation of the free Mg2+ concentration in the in vitro buffer system was used to calibrate its accuracy to that of codon selection by Glu-tRNAGlu in living E. coli cells, previously estimated from the residual activity of a beta-galactosidase mutant in which the codon for an essential Glu had been altered to near cognate codons. At 2.3 mM free Mg2+ concentration, the accuracy in the living cell agreed with that in the test tube, a feature making our biochemistry directly relevant to bacterial physiology. We found that the total accuracy of tRNA selection varied by five orders of magnitude depending on the type of tRNA, type of mismatch and mismatched codon position. We partitioned the total accuracy into initial selection of ternary complex before GTP hydrolysis on EF-Tu and proofreading selection of aminoacyl-tRNA after GTP hydrolysis. We found the contribution of proofreading to be strongly positively correlated with the accuracy of initial selection in its high range. As initial selection decreased further the proofreading contribution to accuracy increased, rather than decreased, a feature neutralizing potentially disastrous missense error hot spots associated with, in particular, tRNAGlu.    

    Emneord
    protein synthesis, genetic code, misreading, error hot spots, kinetics, initial selection, proofreading, total accuracy
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-264957 (URN)
    Tilgjengelig fra: 2015-10-20 Laget: 2015-10-20 Sist oppdatert: 2016-01-13
  • 203.
    Zhang, Jingji
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Enhanced proofreading attenuates initial selection error hot spots in genetic code translation by transfer RNAsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    A system for cell free protein synthesis with E. coli components of high purity was used in conjunction with fast kinetics quench-flow measurements to characterize the accuracy of peptie bond formation by ribosomes with initiator tRNAfMet in P site and different codons in the A site. We used Glu-tRNAGlu, Lys-tRNALys and Phe-tRNAPhe in ternary complexes with EF-Tu and GTP to select ribosomes programmed with their respective cognate codons in competition with ribosomes containing near-cognate codons. Variation of the free Mg2+ concentration in the in vitro buffer system was used to calibrate its accuracy to that of codon selection by Glu-tRNAGlu in living E. coli cells, previously estimated from the residual activity of a beta-galactosidase mutant in which the codon for an essential Glu had been altered to near cognate codons. At 2.3 mM free Mg2+ concentration, the accuracy in the living cell agreed with that in the test tube, a feature making our biochemistry directly relevant to bacterial physiology. We found that the total accuracy of tRNA selection varied by five orders of magnitude depending on the type of tRNA, type of mismatch and mismatched codon position. We partitioned the total accuracy into initial selection of ternary complex before GTP hydrolysis on EF-Tu and proofreading selection of aminoacyl-tRNA after GTP hydrolysis. We found the contribution of proofreading to be strongly positively correlated with the accuracy of initial selection in its high range. As initial selection decreased further the proofreading contribution to accuracy increased, rather than decreased, a feature neutralizing potentially disastrous missense error hot spots associated with, in particular, tRNAGlu.    

  • 204.
    Zhang, Jingji
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    On the mechanism of translation error induction by aminoglycoside antibioticsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We used a cell-free system with pure Escherichia coli components to study how the aminoglycosides disrupt initial codon selection of aminoacyl-tRNAs in ternary complex with elongation factor Tu and GTP by messenger RNA-programmed ribosomes. We take the advantage of the universal rate-accuracy trade-off for all enzymatic selections to determine how the efficiency of initial codon readings decreased linearly toward zero as the accuracy of discrimination against near cognate and wobble codon readings increased toward the maximal asymptote, the effective d value. It turns out two ribosome bound states of ternary complex. First, one codon non-selective step, Mg2+ ions shift the equilibrium from free to ribosome bound ternary complex meaning that the equilibrium between the two ribosome bound complexes is unaltered. Second, codon selective step, aminoglycosides shift the equilibrium from codon non-selective to codon selective complex meaning that the equilibrium between the free and the codon non-selective state is unchanged.

  • 205.
    Zhang, Jingji
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ieong, Ka-Weng
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Johansson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome2015Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 31, s. 9602-9607Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We used a cell-free system with pure Escherichia coli components to study initial codon selection of aminoacyl-tRNAs in ternary complex with elongation factor Tu and GTP on messenger RNA-programmed ribosomes. We took advantage of the universal rate-accuracy trade-off for all enzymatic selections to determine how the efficiency of initial codon readings decreased linearly toward zero as the accuracy of discrimination against near-cognate and wobble codon readings increased toward the maximal asymptote, the d value. We report data on the rate-accuracy variation for 7 cognate, 7 wobble, and 56 near-cognate codon readings comprising about 15% of the genetic code. Their d values varied about 400-fold in the 200-80,000 range depending on type of mismatch, mismatch position in the codon, and tRNA isoacceptor type. We identified error hot spots (d = 200) for U:G misreading in second and U:U or G:A misreading in third codon position by His-tRNA(His) and, as also seen in vivo, Glu-tRNA(Glu). We suggest that the proofreading mechanism has evolved to attenuate error hot spots in initial selection such as those found here.

  • 206.
    Zhang, Jingji
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ieong, Ka-Weng
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Johansson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Large accuracy variation in initial codon selection by aminoacyl-tRNAs on the bacterial ribosomeManuskript (preprint) (Annet vitenskapelig)
  • 207.
    Zhang, Jingji
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ieong, Ka-Weng
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Mellenius, Harriet
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Proofreading neutralizes potential error hotspots in genetic code translation by transfer RNAs2016Inngår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 22, nr 6, s. 896-904Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ribosome uses initial and proofreading selection of aminoacyl-tRNAs for accurate protein synthesis. Anomalously high initial misreading in vitro of near-cognate codons by tRNAHis and tRNAGlu suggested potential error hotspots in protein synthesis, but in vivo data suggested their partial neutralization. To clarify the role of proofreading in this error reduction, we varied the Mg2+ ion concentration to calibrate the total accuracy of our cell-free system to that in the living Escherichia coli cell. We found the total accuracy of tRNA selection in our system to vary by five orders of magnitude depending on tRNA identity, type of mismatch, and mismatched codon position. Proofreading and initial selection were positively correlated at high, but uncorrelated at low initial selection, suggesting hyperactivated proofreading as a means to neutralize potentially disastrous initial selection errors.

  • 208.
    Zhang, Li
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Jiang, Wangshu
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Nan, Jie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Almqvist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Huang, Yafei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    The Escherichia coli CysZ is a pH dependent sulfate transporter that can be inhibited by sulfite2014Inngår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1838, nr 7, s. 1809-1816Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Escherichia coli inner membrane protein CysZ mediates the sulfate uptake subsequently utilized for the synthesis of sulfur-containing compounds in cells. Here we report the purification and functional characterization of CysZ. Using Isothermal Titration Calorimetry, we have observed interactions between CysZ and its putative substrate sulfate. Additional sulfur-containing compounds from the cysteine synthesis pathway have also been analyzed for their abilities to interact with CysZ. Our results suggest that CysZ is dedicated to a specific pathway that assimilates sulfate for the synthesis of cysteine. Sulfate uptake via CysZ into E. coil whole cells and proteoliposome offers direct evidence of CysZ being able to mediate sulfate uptake. In addition, the cysteine synthesis pathway intermediate sulfite can interact directly with CysZ with higher affinity than sulfate. The sulfate transport activity is inhibited in the presence of sulfite, suggesting the existence of a feedback inhibition mechanism in which sulfite regulates sulfate uptake by CysZ. Sulfate uptake assays performed at different extracellular pH and in the presence of a proton uncoupler indicate that this uptake is driven by the proton gradient. (C) 2014 Elsevier B.V. All rights reserved.

  • 209.
    Zhang, Yanqing
    et al.
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Mandava, Chandra Sekhar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Cao, Wei
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Li, Xiaojing
    Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China..
    Zhang, Dejiu
    Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing 100080, Peoples R China..
    Li, Ningning
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Zhang, Yiudao
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Zhang, Xiaoxiao
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Qin, Yan
    Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing 100080, Peoples R China..
    Mi, Kaixia
    Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China..
    Lei, Jianlin
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Sanyal, Suparna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Gao, Ning
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    HflX is a ribosome-splitting factor rescuing stalled ribosomes under stress conditions2015Inngår i: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 22, nr 11, s. 906-913Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adverse cellular conditions often lead to nonproductive translational stalling and arrest of ribosomes on mRNAs. Here, we used fast kinetics and cryo-EM to characterize Escherichia coil HflX, a GTPase with unknown function. Our data reveal that HflX is a heat shock-induced ribosome-splitting factor capable of dissociating vacant as well as mRNA-associated ribosomes with deacylated tRNA in the peptidyl site. Structural data demonstrate that the N-terminal effector domain of HflX binds to the peptidyl transferase center in a strikingly similar manner as that of the class I release factors and induces dramatic conformational changes in central intersubunit bridges, thus promoting subunit dissociation. Accordingly, loss of HflX results in an increase in stalled ribosomes upon heat shock, These results suggest a primary role of HflX in rescuing translationally arrested ribosomes under stress conditions.

  • 210.
    Öhrngren, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wu, Xiongyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Persson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ekegren, Jenny
    Wallberg, Hans
    Vrang, Lotta
    Rosenquist, Åsa
    Samuelsson, Bertil
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents2011Inngår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, nr 8, s. 701-709Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.

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