Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence
Identifieur interne : 003618 ( Ncbi/Merge ); précédent : 003617; suivant : 003619Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence
Auteurs : Grant D. Schauer [États-Unis] ; Kelly D. Huber [États-Unis] ; Sanford H. Leuba [États-Unis] ; Nicolas Sluis-Cremer [États-Unis]Source :
- Nucleic Acids Research [ 0305-1048 ] ; 2014.
Descripteurs français
- KwdFr :
- Amorces ADN, Benzoxazines (pharmacologie), Désoxyribonucléotides (métabolisme), Inhibiteurs de la transcriptase inverse (pharmacologie), Matrices (génétique), Mutation, Polarisation de fluorescence, Régulation allostérique, Sous-unités de protéines (), Transcriptase inverse du VIH (), Transcriptase inverse du VIH (antagonistes et inhibiteurs), Transcriptase inverse du VIH (génétique), Transcriptase inverse du VIH (métabolisme).
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- génétique : Transcriptase inverse du VIH.
- métabolisme : Désoxyribonucléotides, Transcriptase inverse du VIH.
- pharmacologie : Benzoxazines, Inhibiteurs de la transcriptase inverse.
- Amorces ADN, Matrices (génétique), Mutation, Polarisation de fluorescence, Régulation allostérique, Sous-unités de protéines, Transcriptase inverse du VIH.
English descriptors
- KwdEn :
- Allosteric Regulation, Benzoxazines (pharmacology), DNA Primers, Deoxyribonucleotides (metabolism), Fluorescence Polarization, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (chemistry), HIV Reverse Transcriptase (genetics), HIV Reverse Transcriptase (metabolism), Mutation, Protein Subunits (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Templates, Genetic.
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemistry : HIV Reverse Transcriptase, Protein Subunits.
- chemical , genetics : HIV Reverse Transcriptase.
- chemical , metabolism : Deoxyribonucleotides, HIV Reverse Transcriptase.
- chemical , pharmacology : Benzoxazines, Reverse Transcriptase Inhibitors.
- Allosteric Regulation, DNA Primers, Fluorescence Polarization, Mutation, Templates, Genetic.
Abstract
Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are routinely used to treat HIV-1 infection, yet their mechanism of action remains unclear despite intensive investigation. In this study, we developed complementary single-molecule fluorescence and ensemble fluorescence anisotropy approaches to discover how NNRTIs modulate the intra-molecular conformational changes and inter-molecular dynamics of RT-template/primer (T/P) and RT–T/P–dNTP complexes. We found that NNRTI binding to RT induces opening of the fingers and thumb subdomains, which increases the dynamic sliding motion of the enzyme on the T/P and reduces dNTP binding affinity. Further, efavirenz promotes formation of the E138-K101 salt bridge between the p51 and p66 subunits of RT, which contributes to opening of the thumb/fingers subdomains. Engineering a more polar salt bridge between p51 and p66 resulted in even greater increases in the thumb/fingers opening, RT sliding, dNTP binding disruption and
Url:
DOI: 10.1093/nar/gku819
PubMed: 25232099
PubMed Central: 4191400
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Huber</name><affiliation wicri:level="2"><nlm:aff id="AFF3">Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Leuba, Sanford H" sort="Leuba, Sanford H" uniqKey="Leuba S" first="Sanford H." last="Leuba">Sanford H. 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type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Sluis Cremer, Nicolas" sort="Sluis Cremer, Nicolas" uniqKey="Sluis Cremer N" first="Nicolas" last="Sluis-Cremer">Nicolas Sluis-Cremer</name><affiliation wicri:level="2"><nlm:aff id="AFF3">Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">Nucleic Acids Research</title><idno type="ISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Allosteric Regulation</term><term>Benzoxazines (pharmacology)</term><term>DNA Primers</term><term>Deoxyribonucleotides (metabolism)</term><term>Fluorescence Polarization</term><term>HIV Reverse Transcriptase (antagonists & inhibitors)</term><term>HIV Reverse Transcriptase (chemistry)</term><term>HIV Reverse Transcriptase (genetics)</term><term>HIV Reverse Transcriptase (metabolism)</term><term>Mutation</term><term>Protein Subunits (chemistry)</term><term>Reverse Transcriptase Inhibitors (pharmacology)</term><term>Templates, Genetic</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Amorces ADN</term><term>Benzoxazines (pharmacologie)</term><term>Désoxyribonucléotides (métabolisme)</term><term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term><term>Matrices (génétique)</term><term>Mutation</term><term>Polarisation de fluorescence</term><term>Régulation allostérique</term><term>Sous-unités de protéines ()</term><term>Transcriptase inverse du VIH ()</term><term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term><term>Transcriptase inverse du VIH (génétique)</term><term>Transcriptase inverse du VIH (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>HIV Reverse Transcriptase</term><term>Protein Subunits</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Deoxyribonucleotides</term><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Benzoxazines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Désoxyribonucléotides</term><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Benzoxazines</term><term>Inhibiteurs de la transcriptase inverse</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Allosteric Regulation</term><term>DNA Primers</term><term>Fluorescence Polarization</term><term>Mutation</term><term>Templates, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Amorces ADN</term><term>Matrices (génétique)</term><term>Mutation</term><term>Polarisation de fluorescence</term><term>Régulation allostérique</term><term>Sous-unités de protéines</term><term>Transcriptase inverse du VIH</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are routinely used to treat HIV-1 infection, yet their mechanism of action remains unclear despite intensive investigation. In this study, we developed complementary single-molecule fluorescence and ensemble fluorescence anisotropy approaches to discover how NNRTIs modulate the intra-molecular conformational changes and inter-molecular dynamics of RT-template/primer (T/P) and RT–T/P–dNTP complexes. We found that NNRTI binding to RT induces opening of the fingers and thumb subdomains, which increases the dynamic sliding motion of the enzyme on the T/P and reduces dNTP binding affinity. Further, efavirenz promotes formation of the E138-K101 salt bridge between the p51 and p66 subunits of RT, which contributes to opening of the thumb/fingers subdomains. Engineering a more polar salt bridge between p51 and p66 resulted in even greater increases in the thumb/fingers opening, RT sliding, dNTP binding disruption and <italic>in vitro</italic> and <italic>in vivo</italic> RT inhibition than were observed with wild-type RT. We also observed that K103N, a clinically relevant NNRTI resistance mutation, does not prevent binding between efavirenz and RT-T/P but instead allows formation of a stable and productive RT–T/P–dNTP complex, possibly through disruption of the E138-K101 salt bridge. Collectively, these data describe unique structure–activity–resistance relationships that could be exploited for drug development.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Di Marzo Veronese, F" uniqKey="Di Marzo Veronese F">F. di Marzo Veronese</name></author><author><name sortKey="Copeland, T D" uniqKey="Copeland T">T.D. Copeland</name></author><author><name sortKey="Devico, A L" uniqKey="Devico A">A.L. DeVico</name></author><author><name sortKey="Rahman, R" uniqKey="Rahman R">R. Rahman</name></author><author><name sortKey="Oroszlan, S" uniqKey="Oroszlan S">S. Oroszlan</name></author><author><name sortKey="Gallo, R C" uniqKey="Gallo R">R.C. 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Schauer</name><affiliation wicri:level="2"><nlm:aff id="AFF1">Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="AFF2">Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Huber, Kelly D" sort="Huber, Kelly D" uniqKey="Huber K" first="Kelly D." last="Huber">Kelly D. Huber</name><affiliation wicri:level="2"><nlm:aff id="AFF3">Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Leuba, Sanford H" sort="Leuba, Sanford H" uniqKey="Leuba S" first="Sanford H." last="Leuba">Sanford H. Leuba</name><affiliation wicri:level="2"><nlm:aff id="AFF1">Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="AFF2">Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Sluis Cremer, Nicolas" sort="Sluis Cremer, Nicolas" uniqKey="Sluis Cremer N" first="Nicolas" last="Sluis-Cremer">Nicolas Sluis-Cremer</name><affiliation wicri:level="2"><nlm:aff id="AFF3">Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25232099</idno><idno type="pmc">4191400</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191400</idno><idno type="RBID">PMC:4191400</idno><idno type="doi">10.1093/nar/gku819</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001C21</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001C21</idno><idno type="wicri:Area/Pmc/Curation">001B96</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001B96</idno><idno type="wicri:Area/Pmc/Checkpoint">000D23</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000D23</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence</title><author><name sortKey="Schauer, Grant D" sort="Schauer, Grant D" uniqKey="Schauer G" first="Grant D." last="Schauer">Grant D. Schauer</name><affiliation wicri:level="2"><nlm:aff id="AFF1">Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="AFF2">Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Huber, Kelly D" sort="Huber, Kelly D" uniqKey="Huber K" first="Kelly D." last="Huber">Kelly D. Huber</name><affiliation wicri:level="2"><nlm:aff id="AFF3">Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Leuba, Sanford H" sort="Leuba, Sanford H" uniqKey="Leuba S" first="Sanford H." last="Leuba">Sanford H. Leuba</name><affiliation wicri:level="2"><nlm:aff id="AFF1">Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="AFF2">Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Sluis Cremer, Nicolas" sort="Sluis Cremer, Nicolas" uniqKey="Sluis Cremer N" first="Nicolas" last="Sluis-Cremer">Nicolas Sluis-Cremer</name><affiliation wicri:level="2"><nlm:aff id="AFF3">Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">Nucleic Acids Research</title><idno type="ISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are routinely used to treat HIV-1 infection, yet their mechanism of action remains unclear despite intensive investigation. In this study, we developed complementary single-molecule fluorescence and ensemble fluorescence anisotropy approaches to discover how NNRTIs modulate the intra-molecular conformational changes and inter-molecular dynamics of RT-template/primer (T/P) and RT–T/P–dNTP complexes. We found that NNRTI binding to RT induces opening of the fingers and thumb subdomains, which increases the dynamic sliding motion of the enzyme on the T/P and reduces dNTP binding affinity. Further, efavirenz promotes formation of the E138-K101 salt bridge between the p51 and p66 subunits of RT, which contributes to opening of the thumb/fingers subdomains. Engineering a more polar salt bridge between p51 and p66 resulted in even greater increases in the thumb/fingers opening, RT sliding, dNTP binding disruption and <italic>in vitro</italic> and <italic>in vivo</italic> RT inhibition than were observed with wild-type RT. We also observed that K103N, a clinically relevant NNRTI resistance mutation, does not prevent binding between efavirenz and RT-T/P but instead allows formation of a stable and productive RT–T/P–dNTP complex, possibly through disruption of the E138-K101 salt bridge. Collectively, these data describe unique structure–activity–resistance relationships that could be exploited for drug development.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Di Marzo Veronese, F" uniqKey="Di Marzo Veronese F">F. di Marzo Veronese</name></author><author><name sortKey="Copeland, T D" uniqKey="Copeland T">T.D. Copeland</name></author><author><name sortKey="Devico, A L" uniqKey="Devico A">A.L. DeVico</name></author><author><name sortKey="Rahman, R" uniqKey="Rahman R">R. Rahman</name></author><author><name sortKey="Oroszlan, S" uniqKey="Oroszlan S">S. Oroszlan</name></author><author><name sortKey="Gallo, R C" uniqKey="Gallo R">R.C. 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Ehteshami</name></author><author><name sortKey="Gotte, M" uniqKey="Gotte M">M. Götte</name></author><author><name sortKey="Cosa, G" uniqKey="Cosa G">G. Cosa</name></author></analytic></biblStruct></listBibl></div1></back></TEI></pmc><pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence.</title><author><name sortKey="Schauer, Grant D" sort="Schauer, Grant D" uniqKey="Schauer G" first="Grant D" last="Schauer">Grant D. Schauer</name><affiliation wicri:level="2"><nlm:affiliation>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Huber, Kelly D" sort="Huber, Kelly D" uniqKey="Huber K" first="Kelly D" last="Huber">Kelly D. Huber</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Leuba, Sanford H" sort="Leuba, Sanford H" uniqKey="Leuba S" first="Sanford H" last="Leuba">Sanford H. Leuba</name><affiliation wicri:level="2"><nlm:affiliation>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA leuba@pitt.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Sluis Cremer, Nicolas" sort="Sluis Cremer, Nicolas" uniqKey="Sluis Cremer N" first="Nicolas" last="Sluis-Cremer">Nicolas Sluis-Cremer</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:25232099</idno><idno type="pmid">25232099</idno><idno type="doi">10.1093/nar/gku819</idno><idno type="wicri:Area/PubMed/Corpus">001633</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001633</idno><idno type="wicri:Area/PubMed/Curation">001626</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001626</idno><idno type="wicri:Area/PubMed/Checkpoint">001626</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001626</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence.</title><author><name sortKey="Schauer, Grant D" sort="Schauer, Grant D" uniqKey="Schauer G" first="Grant D" last="Schauer">Grant D. Schauer</name><affiliation wicri:level="2"><nlm:affiliation>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Huber, Kelly D" sort="Huber, Kelly D" uniqKey="Huber K" first="Kelly D" last="Huber">Kelly D. Huber</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Leuba, Sanford H" sort="Leuba, Sanford H" uniqKey="Leuba S" first="Sanford H" last="Leuba">Sanford H. Leuba</name><affiliation wicri:level="2"><nlm:affiliation>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA leuba@pitt.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Cell Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Sluis Cremer, Nicolas" sort="Sluis Cremer, Nicolas" uniqKey="Sluis Cremer N" first="Nicolas" last="Sluis-Cremer">Nicolas Sluis-Cremer</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">Nucleic acids research</title><idno type="eISSN">1362-4962</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Allosteric Regulation</term><term>Benzoxazines (pharmacology)</term><term>DNA Primers</term><term>Deoxyribonucleotides (metabolism)</term><term>Fluorescence Polarization</term><term>HIV Reverse Transcriptase (antagonists & inhibitors)</term><term>HIV Reverse Transcriptase (chemistry)</term><term>HIV Reverse Transcriptase (genetics)</term><term>HIV Reverse Transcriptase (metabolism)</term><term>Mutation</term><term>Protein Subunits (chemistry)</term><term>Reverse Transcriptase Inhibitors (pharmacology)</term><term>Templates, Genetic</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Amorces ADN</term><term>Benzoxazines (pharmacologie)</term><term>Désoxyribonucléotides (métabolisme)</term><term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term><term>Matrices (génétique)</term><term>Mutation</term><term>Polarisation de fluorescence</term><term>Régulation allostérique</term><term>Sous-unités de protéines ()</term><term>Transcriptase inverse du VIH ()</term><term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term><term>Transcriptase inverse du VIH (génétique)</term><term>Transcriptase inverse du VIH (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>HIV Reverse Transcriptase</term><term>Protein Subunits</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Deoxyribonucleotides</term><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Benzoxazines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Désoxyribonucléotides</term><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Benzoxazines</term><term>Inhibiteurs de la transcriptase inverse</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Allosteric Regulation</term><term>DNA Primers</term><term>Fluorescence Polarization</term><term>Mutation</term><term>Templates, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Amorces ADN</term><term>Matrices (génétique)</term><term>Mutation</term><term>Polarisation de fluorescence</term><term>Régulation allostérique</term><term>Sous-unités de protéines</term><term>Transcriptase inverse du VIH</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are routinely used to treat HIV-1 infection, yet their mechanism of action remains unclear despite intensive investigation. In this study, we developed complementary single-molecule fluorescence and ensemble fluorescence anisotropy approaches to discover how NNRTIs modulate the intra-molecular conformational changes and inter-molecular dynamics of RT-template/primer (T/P) and RT-T/P-dNTP complexes. We found that NNRTI binding to RT induces opening of the fingers and thumb subdomains, which increases the dynamic sliding motion of the enzyme on the T/P and reduces dNTP binding affinity. Further, efavirenz promotes formation of the E138-K101 salt bridge between the p51 and p66 subunits of RT, which contributes to opening of the thumb/fingers subdomains. Engineering a more polar salt bridge between p51 and p66 resulted in even greater increases in the thumb/fingers opening, RT sliding, dNTP binding disruption and in vitro and in vivo RT inhibition than were observed with wild-type RT. We also observed that K103N, a clinically relevant NNRTI resistance mutation, does not prevent binding between efavirenz and RT-T/P but instead allows formation of a stable and productive RT-T/P-dNTP complex, possibly through disruption of the E138-K101 salt bridge. Collectively, these data describe unique structure-activity-resistance relationships that could be exploited for drug development.</div></front></TEI></pubmed></double></record>Pour manipuler ce document sous Unix (Dilib)
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