Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design.
Identifieur interne : 005F28 ( Main/Exploration ); précédent : 005F27; suivant : 005F29Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design.
Auteurs : Xiang Xu [République populaire de Chine] ; Yunqing Liu ; Susan Weiss ; Eddy Arnold ; Stefan G. Sarafianos ; Jianping DingSource :
- Nucleic acids research [ 1362-4962 ] ; 2003.
Descripteurs français
- KwdFr :
- Alignement de séquences, Antienzymes (), Antienzymes (pharmacologie), Antiviraux (), Antiviraux (pharmacologie), Conception de médicament, Domaine catalytique, Données de séquences moléculaires, Liaison hydrogène, Modèles moléculaires, Motifs d'acides aminés, RNA replicase (), RNA replicase (antagonistes et inhibiteurs), RNA replicase (métabolisme), Ribavirine (pharmacologie), Résistance virale aux médicaments, Similitude de séquences d'acides aminés, Sites de fixation, Structure tertiaire des protéines, Séquence conservée, Séquence d'acides aminés, Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : RNA replicase.
- enzymologie : Virus du SRAS.
- métabolisme : RNA replicase.
- pharmacologie : Antienzymes, Antiviraux, Ribavirine.
- Alignement de séquences, Antienzymes, Antiviraux, Conception de médicament, Domaine catalytique, Données de séquences moléculaires, Liaison hydrogène, Modèles moléculaires, Motifs d'acides aminés, RNA replicase, Résistance virale aux médicaments, Similitude de séquences d'acides aminés, Sites de fixation, Structure tertiaire des protéines, Séquence conservée, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Motifs, Amino Acid Sequence, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Binding Sites, Catalytic Domain, Conserved Sequence, Drug Design, Drug Resistance, Viral, Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, RNA Replicase (antagonists & inhibitors), RNA Replicase (chemistry), RNA Replicase (metabolism), Ribavirin (pharmacology), SARS Virus (enzymology), Sequence Alignment, Sequence Homology, Amino Acid.
- MESH :
- chemical , antagonists & inhibitors : RNA Replicase.
- chemical , chemistry : Antiviral Agents, Enzyme Inhibitors, RNA Replicase.
- chemical , metabolism : RNA Replicase.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors, Ribavirin.
- enzymology : SARS Virus.
- Amino Acid Motifs, Amino Acid Sequence, Binding Sites, Catalytic Domain, Conserved Sequence, Drug Design, Drug Resistance, Viral, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Sequence Alignment, Sequence Homology, Amino Acid.
Abstract
The causative agent of severe acute respiratory syndrome (SARS) is a previously unidentified coronavirus, SARS-CoV. The RNA-dependent RNA polymerase (RdRp) of SARS-CoV plays a pivotal role in viral replication and is a potential target for anti-SARS therapy. There is a lack of structural or biochemical data on any coronavirus polymerase. To provide insights into the structure and function of SARS-CoV RdRp, we have located its conserved motifs that are shared by all RdRps, and built a three-dimensional model of the catalytic domain. The structural model permits us to discuss the potential functional roles of the conserved motifs and residues in replication and their potential interactions with inhibitors of related enzymes. We predict important structural attributes of potential anti-SARS-CoV RdRp nucleotide analog inhibitors: hydrogen-bonding capability for the 2' and 3' groups of the sugar ring and C3' endo sugar puckering, and the absence of a hydrophobic binding pocket for non-nucleoside analog inhibitors similar to those observed in hepatitis C virus RdRp and human immunodeficiency virus type 1 reverse transcriptase. We propose that the clinically observed resistance of SARS to ribavirin is probably due to perturbation of the conserved motif A that controls rNTP binding and fidelity of polymerization. Our results suggest that designing anti-SARS therapies can benefit from successful experiences in design of other antiviral drugs. This work should also provide guidance for future biochemical experiments.
DOI: 10.1093/nar/gkg916
PubMed: 14654687
Affiliations:
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Le document en format XML
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Sarafianos</name></author><author><name sortKey="Ding, Jianping" sort="Ding, Jianping" uniqKey="Ding J" first="Jianping" last="Ding">Jianping Ding</name></author></analytic><series><title level="j">Nucleic acids research</title><idno type="eISSN">1362-4962</idno><imprint><date when="2003" type="published">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Motifs</term><term>Amino Acid Sequence</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Binding Sites</term><term>Catalytic Domain</term><term>Conserved Sequence</term><term>Drug Design</term><term>Drug Resistance, Viral</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Hydrogen Bonding</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Protein Structure, Tertiary</term><term>RNA Replicase (antagonists & inhibitors)</term><term>RNA Replicase (chemistry)</term><term>RNA Replicase (metabolism)</term><term>Ribavirin (pharmacology)</term><term>SARS Virus (enzymology)</term><term>Sequence Alignment</term><term>Sequence Homology, Amino Acid</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Alignement de séquences</term><term>Antienzymes ()</term><term>Antienzymes (pharmacologie)</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Conception de médicament</term><term>Domaine catalytique</term><term>Données de séquences moléculaires</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Motifs d'acides aminés</term><term>RNA replicase ()</term><term>RNA replicase (antagonistes et inhibiteurs)</term><term>RNA replicase (métabolisme)</term><term>Ribavirine (pharmacologie)</term><term>Résistance virale aux médicaments</term><term>Similitude de séquences d'acides aminés</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Séquence conservée</term><term>Séquence d'acides aminés</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>RNA Replicase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>RNA Replicase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>RNA Replicase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>Ribavirin</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>RNA replicase</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>RNA replicase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term><term>Antiviraux</term><term>Ribavirine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Motifs</term><term>Amino Acid Sequence</term><term>Binding Sites</term><term>Catalytic Domain</term><term>Conserved Sequence</term><term>Drug Design</term><term>Drug Resistance, Viral</term><term>Hydrogen Bonding</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Protein Structure, Tertiary</term><term>Sequence Alignment</term><term>Sequence Homology, Amino Acid</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term><term>Antienzymes</term><term>Antiviraux</term><term>Conception de médicament</term><term>Domaine catalytique</term><term>Données de séquences moléculaires</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Motifs d'acides aminés</term><term>RNA replicase</term><term>Résistance virale aux médicaments</term><term>Similitude de séquences d'acides aminés</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Séquence conservée</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The causative agent of severe acute respiratory syndrome (SARS) is a previously unidentified coronavirus, SARS-CoV. The RNA-dependent RNA polymerase (RdRp) of SARS-CoV plays a pivotal role in viral replication and is a potential target for anti-SARS therapy. There is a lack of structural or biochemical data on any coronavirus polymerase. To provide insights into the structure and function of SARS-CoV RdRp, we have located its conserved motifs that are shared by all RdRps, and built a three-dimensional model of the catalytic domain. The structural model permits us to discuss the potential functional roles of the conserved motifs and residues in replication and their potential interactions with inhibitors of related enzymes. We predict important structural attributes of potential anti-SARS-CoV RdRp nucleotide analog inhibitors: hydrogen-bonding capability for the 2' and 3' groups of the sugar ring and C3' endo sugar puckering, and the absence of a hydrophobic binding pocket for non-nucleoside analog inhibitors similar to those observed in hepatitis C virus RdRp and human immunodeficiency virus type 1 reverse transcriptase. We propose that the clinically observed resistance of SARS to ribavirin is probably due to perturbation of the conserved motif A that controls rNTP binding and fidelity of polymerization. Our results suggest that designing anti-SARS therapies can benefit from successful experiences in design of other antiviral drugs. This work should also provide guidance for future biochemical experiments.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><noCountry><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><name sortKey="Ding, Jianping" sort="Ding, Jianping" uniqKey="Ding J" first="Jianping" last="Ding">Jianping Ding</name><name sortKey="Liu, Yunqing" sort="Liu, Yunqing" uniqKey="Liu Y" first="Yunqing" last="Liu">Yunqing Liu</name><name sortKey="Sarafianos, Stefan G" sort="Sarafianos, Stefan G" uniqKey="Sarafianos S" first="Stefan G" last="Sarafianos">Stefan G. Sarafianos</name><name sortKey="Weiss, Susan" sort="Weiss, Susan" uniqKey="Weiss S" first="Susan" last="Weiss">Susan Weiss</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Xu, Xiang" sort="Xu, Xiang" uniqKey="Xu X" first="Xiang" last="Xu">Xiang Xu</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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