Insight into the activity of SARS main protease: Molecular dynamics study of dimeric and monomeric form of enzyme.
Identifieur interne : 003671 ( Main/Exploration ); précédent : 003670; suivant : 003672Insight into the activity of SARS main protease: Molecular dynamics study of dimeric and monomeric form of enzyme.
Auteurs : Kewen Zheng [République populaire de Chine] ; Guozheng Ma ; Jinming Zhou ; Min Zen ; Wenna Zhao ; Yongjun Jiang ; Qingsen Yu ; Jialiang FengSource :
- Proteins [ 1097-0134 ] ; 2007.
Descripteurs français
- KwdFr :
- Cartographie d'interactions entre protéines, Conformation des protéines, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Dimérisation, Domaine catalytique, Eau, Hydrolyse, Inhibiteurs de protéases (pharmacologie), Liaison hydrogène, Modèles chimiques, Modèles moléculaires, Protéines virales (), Protéines virales (métabolisme), Relation structure-activité, Simulation numérique, Spécificité du substrat, Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases, Protéines virales.
- pharmacologie : Inhibiteurs de protéases.
- Cartographie d'interactions entre protéines, Conformation des protéines, Cysteine endopeptidases, Dimérisation, Domaine catalytique, Eau, Hydrolyse, Liaison hydrogène, Modèles chimiques, Modèles moléculaires, Protéines virales, Relation structure-activité, Simulation numérique, Spécificité du substrat.
English descriptors
- KwdEn :
- Catalytic Domain, Computer Simulation, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Dimerization, Hydrogen Bonding, Hydrolysis, Models, Chemical, Models, Molecular, Protease Inhibitors (pharmacology), Protein Conformation, Protein Interaction Mapping, SARS Virus (enzymology), Structure-Activity Relationship, Substrate Specificity, Viral Proteins (chemistry), Viral Proteins (metabolism), Water.
- MESH :
- chemical , chemistry : Cysteine Endopeptidases, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Viral Proteins.
- chemical , pharmacology : Protease Inhibitors.
- enzymology : SARS Virus.
- Catalytic Domain, Computer Simulation, Dimerization, Hydrogen Bonding, Hydrolysis, Models, Chemical, Models, Molecular, Protein Conformation, Protein Interaction Mapping, Structure-Activity Relationship, Substrate Specificity, Water.
Abstract
The phenomenon that SARS coronavirus main protease (SARS M(pro)) dimer is the main functional form has been confirmed by experiment. However, because of the absence of structural information of the monomer, the reasons for this remain unknown. To investigate it, two molecular dynamics (MD) simulations in water for dimer and monomer models have been carried out, using the crystal structure of protomer A of the dimer as the starting structure for the monomer. During the MD simulation of dimer, three interest phenomena of protomer A have been observed: (i) the distance between NE2 of His41 and SG of Cys145 averages 3.72 A, which agrees well with the experimental observations made by X-ray crystallography; (ii) His163 and Glu166 form the "tooth" conformational properties, resulting in the specificity for glutamine at substrate P1 site; and (iii) the substrate-binding pocket formed by loop 140-146 and loop 184-197 is large enough to accommodate the substrate analog. However, during the MD simulation of the monomer complex, the three structural characteristics are all absent, which results directly in the inactivation of the monomer. Throughout the MD simulation of the dimer, the N-terminus of protomer B forms stable hydrogen bonds with Phe140 and Glu166, through which His163, Glu166, and loop 140-146 are kept active form. Furthermore, a water-bridge has been found between the N-terminus of protomer B and Gly170, which stabilizes His172 and avoids it moving toward Tyr161 to disrupt the H-bond between Tyr161 and His163, stabilizing the conformation of His163. The interactions between the N-terminus and another monomer maintain the activity of dimer.
DOI: 10.1002/prot.21160
PubMed: 17083088
Affiliations:
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Zheng</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200072, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200072</wicri:regionArea><wicri:noRegion>Shanghai 200072</wicri:noRegion></affiliation></author><author><name sortKey="Ma, Guozheng" sort="Ma, Guozheng" uniqKey="Ma G" first="Guozheng" last="Ma">Guozheng Ma</name></author><author><name sortKey="Zhou, Jinming" sort="Zhou, Jinming" uniqKey="Zhou J" first="Jinming" last="Zhou">Jinming Zhou</name></author><author><name sortKey="Zen, Min" sort="Zen, Min" uniqKey="Zen M" first="Min" last="Zen">Min Zen</name></author><author><name sortKey="Zhao, Wenna" sort="Zhao, Wenna" uniqKey="Zhao W" first="Wenna" last="Zhao">Wenna Zhao</name></author><author><name sortKey="Jiang, Yongjun" sort="Jiang, Yongjun" uniqKey="Jiang Y" first="Yongjun" last="Jiang">Yongjun Jiang</name></author><author><name sortKey="Yu, Qingsen" sort="Yu, Qingsen" uniqKey="Yu Q" first="Qingsen" last="Yu">Qingsen Yu</name></author><author><name sortKey="Feng, Jialiang" sort="Feng, Jialiang" uniqKey="Feng J" first="Jialiang" last="Feng">Jialiang Feng</name></author></analytic><series><title level="j">Proteins</title><idno type="eISSN">1097-0134</idno><imprint><date when="2007" type="published">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Catalytic Domain</term><term>Computer Simulation</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Dimerization</term><term>Hydrogen Bonding</term><term>Hydrolysis</term><term>Models, Chemical</term><term>Models, Molecular</term><term>Protease Inhibitors (pharmacology)</term><term>Protein Conformation</term><term>Protein Interaction Mapping</term><term>SARS Virus (enzymology)</term><term>Structure-Activity Relationship</term><term>Substrate Specificity</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (metabolism)</term><term>Water</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cartographie d'interactions entre protéines</term><term>Conformation des protéines</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (métabolisme)</term><term>Dimérisation</term><term>Domaine catalytique</term><term>Eau</term><term>Hydrolyse</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Liaison hydrogène</term><term>Modèles chimiques</term><term>Modèles moléculaires</term><term>Protéines virales ()</term><term>Protéines virales (métabolisme)</term><term>Relation structure-activité</term><term>Simulation numérique</term><term>Spécificité du substrat</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Protease Inhibitors</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>Cysteine endopeptidases</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term><term>Computer Simulation</term><term>Dimerization</term><term>Hydrogen Bonding</term><term>Hydrolysis</term><term>Models, Chemical</term><term>Models, Molecular</term><term>Protein Conformation</term><term>Protein Interaction Mapping</term><term>Structure-Activity Relationship</term><term>Substrate Specificity</term><term>Water</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cartographie d'interactions entre protéines</term><term>Conformation des protéines</term><term>Cysteine endopeptidases</term><term>Dimérisation</term><term>Domaine catalytique</term><term>Eau</term><term>Hydrolyse</term><term>Liaison hydrogène</term><term>Modèles chimiques</term><term>Modèles moléculaires</term><term>Protéines virales</term><term>Relation structure-activité</term><term>Simulation numérique</term><term>Spécificité du substrat</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The phenomenon that SARS coronavirus main protease (SARS M(pro)) dimer is the main functional form has been confirmed by experiment. However, because of the absence of structural information of the monomer, the reasons for this remain unknown. To investigate it, two molecular dynamics (MD) simulations in water for dimer and monomer models have been carried out, using the crystal structure of protomer A of the dimer as the starting structure for the monomer. During the MD simulation of dimer, three interest phenomena of protomer A have been observed: (i) the distance between NE2 of His41 and SG of Cys145 averages 3.72 A, which agrees well with the experimental observations made by X-ray crystallography; (ii) His163 and Glu166 form the "tooth" conformational properties, resulting in the specificity for glutamine at substrate P1 site; and (iii) the substrate-binding pocket formed by loop 140-146 and loop 184-197 is large enough to accommodate the substrate analog. However, during the MD simulation of the monomer complex, the three structural characteristics are all absent, which results directly in the inactivation of the monomer. Throughout the MD simulation of the dimer, the N-terminus of protomer B forms stable hydrogen bonds with Phe140 and Glu166, through which His163, Glu166, and loop 140-146 are kept active form. Furthermore, a water-bridge has been found between the N-terminus of protomer B and Gly170, which stabilizes His172 and avoids it moving toward Tyr161 to disrupt the H-bond between Tyr161 and His163, stabilizing the conformation of His163. The interactions between the N-terminus and another monomer maintain the activity of dimer.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><noCountry><name sortKey="Feng, Jialiang" sort="Feng, Jialiang" uniqKey="Feng J" first="Jialiang" last="Feng">Jialiang Feng</name><name sortKey="Jiang, Yongjun" sort="Jiang, Yongjun" uniqKey="Jiang Y" first="Yongjun" last="Jiang">Yongjun Jiang</name><name sortKey="Ma, Guozheng" sort="Ma, Guozheng" uniqKey="Ma G" first="Guozheng" last="Ma">Guozheng Ma</name><name sortKey="Yu, Qingsen" sort="Yu, Qingsen" uniqKey="Yu Q" first="Qingsen" last="Yu">Qingsen Yu</name><name sortKey="Zen, Min" sort="Zen, Min" uniqKey="Zen M" first="Min" last="Zen">Min Zen</name><name sortKey="Zhao, Wenna" sort="Zhao, Wenna" uniqKey="Zhao W" first="Wenna" last="Zhao">Wenna Zhao</name><name sortKey="Zhou, Jinming" sort="Zhou, Jinming" uniqKey="Zhou J" first="Jinming" last="Zhou">Jinming Zhou</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Zheng, Kewen" sort="Zheng, Kewen" uniqKey="Zheng K" first="Kewen" last="Zheng">Kewen Zheng</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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