Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: catalytic efficiency regulated by substrate binding.
Identifieur interne : 005365 ( Main/Merge ); précédent : 005364; suivant : 005366Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: catalytic efficiency regulated by substrate binding.
Auteurs : Yuan-Ping Pang [États-Unis]Source :
- Proteins [ 1097-0134 ] ; 2004.
Descripteurs français
- KwdFr :
- Acetylcholinesterase (), Alignement de séquences, Antienzymes, Catalyse, Cristallographie aux rayons X, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Données de séquences moléculaires, Liaison aux protéines, Modèles moléculaires, Similitude structurale de protéines, Simulation numérique, Sites de fixation, Structure tertiaire des protéines, Séquence d'acides aminés, Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases.
- Acetylcholinesterase, Alignement de séquences, Antienzymes, Catalyse, Cristallographie aux rayons X, Cysteine endopeptidases, Données de séquences moléculaires, Liaison aux protéines, Modèles moléculaires, Similitude structurale de protéines, Simulation numérique, Sites de fixation, Structure tertiaire des protéines, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Acetylcholinesterase (chemistry), Amino Acid Sequence, Binding Sites, Catalysis, Computer Simulation, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Enzyme Inhibitors, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, SARS Virus (enzymology), Sequence Alignment, Structural Homology, Protein.
- MESH :
- chemical , chemistry : Acetylcholinesterase, Cysteine Endopeptidases.
- chemical , metabolism : Cysteine Endopeptidases.
- enzymology : SARS Virus.
- Amino Acid Sequence, Binding Sites, Catalysis, Computer Simulation, Crystallography, X-Ray, Enzyme Inhibitors, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Sequence Alignment, Structural Homology, Protein.
Abstract
Severe acute respiratory syndrome (SARS) is a contagious and deadly disease caused by a new coronavirus. The protein sequence of the chymotrypsin-like cysteine proteinase (CCP) responsible for SARS viral replication has been identified as a target for developing anti-SARS drugs. Here, I report the ATVRLQ(p1)A(p1')-bound CCP 3D model predicted by 420 different molecular dynamics simulations (2.0 ns for each simulation with a 1.0-fs time step). This theoretical model was released at the Protein Data Bank (PDB; code: 1P76) before the release of the first X-ray structure of CCP (PDB code: 1Q2W). In contrast to the catalytic dyad observed in X-ray structures of CCP and other coronavirus cysteine proteinases, a catalytic triad comprising Asp187, His41, and Cys145 is found in the theoretical model of the substrate-bound CCP. The simulations of the CCP complex suggest that substrate binding leads to the displacement of a water molecule entrapped by Asp187 and His41, thus converting the dyad to a more efficient catalytic triad. The CCP complex structure has an expanded active-site pocket that is useful for anti-SARS drug design. In addition, this work demonstrates that multiple molecular dynamics simulations are effective in correcting errors that result from low-sequence-identity homology modeling.
DOI: 10.1002/prot.20249
PubMed: 15690493
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pubmed:15690493Le document en format XML
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sortKey="Pang, Yuan Ping" sort="Pang, Yuan Ping" uniqKey="Pang Y" first="Yuan-Ping" last="Pang">Yuan-Ping Pang</name><affiliation wicri:level="1"><nlm:affiliation>Computer-Aided Molecular Design Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. pang@mayo.edu</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Computer-Aided Molecular Design Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota 55905</wicri:regionArea><wicri:noRegion>Minnesota 55905</wicri:noRegion></affiliation></author></analytic><series><title level="j">Proteins</title><idno type="eISSN">1097-0134</idno><imprint><date when="2004" type="published">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetylcholinesterase (chemistry)</term><term>Amino Acid Sequence</term><term>Binding Sites</term><term>Catalysis</term><term>Computer Simulation</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Enzyme Inhibitors</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>SARS Virus (enzymology)</term><term>Sequence Alignment</term><term>Structural Homology, Protein</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acetylcholinesterase ()</term><term>Alignement de séquences</term><term>Antienzymes</term><term>Catalyse</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (métabolisme)</term><term>Données de séquences moléculaires</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Similitude structurale de protéines</term><term>Simulation numérique</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Séquence d'acides aminés</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Acetylcholinesterase</term><term>Cysteine Endopeptidases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</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></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Binding Sites</term><term>Catalysis</term><term>Computer Simulation</term><term>Crystallography, X-Ray</term><term>Enzyme Inhibitors</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Sequence Alignment</term><term>Structural Homology, Protein</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acetylcholinesterase</term><term>Alignement de séquences</term><term>Antienzymes</term><term>Catalyse</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Données de séquences moléculaires</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Similitude structurale de protéines</term><term>Simulation numérique</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is a contagious and deadly disease caused by a new coronavirus. The protein sequence of the chymotrypsin-like cysteine proteinase (CCP) responsible for SARS viral replication has been identified as a target for developing anti-SARS drugs. Here, I report the ATVRLQ(p1)A(p1')-bound CCP 3D model predicted by 420 different molecular dynamics simulations (2.0 ns for each simulation with a 1.0-fs time step). This theoretical model was released at the Protein Data Bank (PDB; code: 1P76) before the release of the first X-ray structure of CCP (PDB code: 1Q2W). In contrast to the catalytic dyad observed in X-ray structures of CCP and other coronavirus cysteine proteinases, a catalytic triad comprising Asp187, His41, and Cys145 is found in the theoretical model of the substrate-bound CCP. The simulations of the CCP complex suggest that substrate binding leads to the displacement of a water molecule entrapped by Asp187 and His41, thus converting the dyad to a more efficient catalytic triad. The CCP complex structure has an expanded active-site pocket that is useful for anti-SARS drug design. In addition, this work demonstrates that multiple molecular dynamics simulations are effective in correcting errors that result from low-sequence-identity homology modeling.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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