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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PMC:4191400Le document en format XML
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<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>
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<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>
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<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>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Reverse Transcriptase</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Deoxyribonucleotides</term>
<term>HIV Reverse Transcriptase</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Benzoxazines</term>
<term>Reverse Transcriptase Inhibitors</term>
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<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
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<term>Transcriptase inverse du VIH</term>
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<term>Inhibiteurs de la transcriptase inverse</term>
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<term>Templates, Genetic</term>
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<term>Mutation</term>
<term>Polarisation de fluorescence</term>
<term>Régulation allostérique</term>
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<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>
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<double pmid="25232099"><pmc><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: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>
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<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>
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</author>
<author><name sortKey="Leuba, Sanford H" sort="Leuba, Sanford H" uniqKey="Leuba S" first="Sanford H." last="Leuba">Sanford H. Leuba</name>
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<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>
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<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>
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<idno type="doi">10.1093/nar/gku819</idno>
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<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>
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<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>
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<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>
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