Mechanism for controlling the monomer-dimer conversion of SARS coronavirus main protease.
Identifieur interne : 001903 ( Main/Exploration ); précédent : 001902; suivant : 001904Mechanism for controlling the monomer-dimer conversion of SARS coronavirus main protease.
Auteurs : Cheng Guo Wu [Taïwan] ; Shu Chun Cheng ; Shiang Chuan Chen ; Juo Yan Li ; Yi Hsuan Fang ; Yau Hung Chen ; Chi Yuan ChouSource :
- Acta crystallographica. Section D, Biological crystallography [ 1399-0047 ] ; 2013.
Descripteurs français
- KwdFr :
- Conformation des protéines, Cristallographie aux rayons X, Cysteine endopeptidases (), Cysteine endopeptidases (génétique), Cysteine endopeptidases (métabolisme), Modèles moléculaires, Multimérisation de protéines, Mutation, Protéines de la matrice virale (), Protéines de la matrice virale (génétique), Protéines de la matrice virale (métabolisme), Protéines virales (), Protéines virales (génétique), Protéines virales (métabolisme), Sites de fixation, Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Virus du SRAS.
- génétique : Cysteine endopeptidases, Protéines de la matrice virale, Protéines virales.
- métabolisme : Cysteine endopeptidases, Protéines de la matrice virale, Protéines virales.
- Conformation des protéines, Cristallographie aux rayons X, Cysteine endopeptidases, Modèles moléculaires, Multimérisation de protéines, Mutation, Protéines de la matrice virale, Protéines virales, Sites de fixation, Virus du SRAS.
English descriptors
- KwdEn :
- Binding Sites, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (genetics), Cysteine Endopeptidases (metabolism), Models, Molecular, Mutation, Protein Conformation, Protein Multimerization, SARS Virus (chemistry), SARS Virus (enzymology), Viral Matrix Proteins (chemistry), Viral Matrix Proteins (genetics), Viral Matrix Proteins (metabolism), Viral Proteins (chemistry), Viral Proteins (genetics), Viral Proteins (metabolism).
- MESH :
- chemical , chemistry : Cysteine Endopeptidases, Viral Matrix Proteins, Viral Proteins.
- chemical , genetics : Cysteine Endopeptidases, Viral Matrix Proteins, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Viral Matrix Proteins, Viral Proteins.
- chemistry : SARS Virus.
- enzymology : SARS Virus.
- Binding Sites, Crystallography, X-Ray, Models, Molecular, Mutation, Protein Conformation, Protein Multimerization.
Abstract
The Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)) cleaves two virion polyproteins (pp1a and pp1ab); this essential process represents an attractive target for the development of anti-SARS drugs. The functional unit of M(pro) is a homodimer and each subunit contains a His41/Cys145 catalytic dyad. Large amounts of biochemical and structural information are available on M(pro); nevertheless, the mechanism by which monomeric M(pro) is converted into a dimer during maturation still remains poorly understood. Previous studies have suggested that a C-terminal residue, Arg298, interacts with Ser123 of the other monomer in the dimer, and mutation of Arg298 results in a monomeric structure with a collapsed substrate-binding pocket. Interestingly, the R298A mutant of M(pro) shows a reversible substrate-induced dimerization that is essential for catalysis. Here, the conformational change that occurs during substrate-induced dimerization is delineated by X-ray crystallography. A dimer with a mutual orientation of the monomers that differs from that of the wild-type protease is present in the asymmetric unit. The presence of a complete substrate-binding pocket and oxyanion hole in both protomers suggests that they are both catalytically active, while the two domain IIIs show minor reorganization. This structural information offers valuable insights into the molecular mechanism associated with substrate-induced dimerization and has important implications with respect to the maturation of the enzyme.
DOI: 10.1107/S0907444913001315
PubMed: 23633583
Affiliations:
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Le document en format XML
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Section D, Biological crystallography</title><idno type="eISSN">1399-0047</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (genetics)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Models, Molecular</term><term>Mutation</term><term>Protein Conformation</term><term>Protein Multimerization</term><term>SARS Virus (chemistry)</term><term>SARS Virus (enzymology)</term><term>Viral Matrix Proteins (chemistry)</term><term>Viral Matrix Proteins (genetics)</term><term>Viral Matrix Proteins (metabolism)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (genetics)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Conformation des protéines</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (génétique)</term><term>Cysteine endopeptidases (métabolisme)</term><term>Modèles moléculaires</term><term>Multimérisation de protéines</term><term>Mutation</term><term>Protéines de la matrice virale ()</term><term>Protéines de la matrice virale (génétique)</term><term>Protéines de la matrice virale (métabolisme)</term><term>Protéines virales ()</term><term>Protéines virales (génétique)</term><term>Protéines virales (métabolisme)</term><term>Sites de fixation</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Matrix Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Matrix Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Matrix Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</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="génétique" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Protéines de la matrice virale</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Protéines de la matrice virale</term><term>Protéines virales</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Crystallography, X-Ray</term><term>Models, Molecular</term><term>Mutation</term><term>Protein Conformation</term><term>Protein Multimerization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Conformation des protéines</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Modèles moléculaires</term><term>Multimérisation de protéines</term><term>Mutation</term><term>Protéines de la matrice virale</term><term>Protéines virales</term><term>Sites de fixation</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)) cleaves two virion polyproteins (pp1a and pp1ab); this essential process represents an attractive target for the development of anti-SARS drugs. The functional unit of M(pro) is a homodimer and each subunit contains a His41/Cys145 catalytic dyad. Large amounts of biochemical and structural information are available on M(pro); nevertheless, the mechanism by which monomeric M(pro) is converted into a dimer during maturation still remains poorly understood. Previous studies have suggested that a C-terminal residue, Arg298, interacts with Ser123 of the other monomer in the dimer, and mutation of Arg298 results in a monomeric structure with a collapsed substrate-binding pocket. Interestingly, the R298A mutant of M(pro) shows a reversible substrate-induced dimerization that is essential for catalysis. Here, the conformational change that occurs during substrate-induced dimerization is delineated by X-ray crystallography. A dimer with a mutual orientation of the monomers that differs from that of the wild-type protease is present in the asymmetric unit. The presence of a complete substrate-binding pocket and oxyanion hole in both protomers suggests that they are both catalytically active, while the two domain IIIs show minor reorganization. This structural information offers valuable insights into the molecular mechanism associated with substrate-induced dimerization and has important implications with respect to the maturation of the enzyme.</div></front></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><noCountry><name sortKey="Chen, Shiang Chuan" sort="Chen, Shiang Chuan" uniqKey="Chen S" first="Shiang Chuan" last="Chen">Shiang Chuan Chen</name><name sortKey="Chen, Yau Hung" sort="Chen, Yau Hung" uniqKey="Chen Y" first="Yau Hung" last="Chen">Yau Hung Chen</name><name sortKey="Cheng, Shu Chun" sort="Cheng, Shu Chun" uniqKey="Cheng S" first="Shu Chun" last="Cheng">Shu Chun Cheng</name><name sortKey="Chou, Chi Yuan" sort="Chou, Chi Yuan" uniqKey="Chou C" first="Chi Yuan" last="Chou">Chi Yuan Chou</name><name sortKey="Fang, Yi Hsuan" sort="Fang, Yi Hsuan" uniqKey="Fang Y" first="Yi Hsuan" last="Fang">Yi Hsuan Fang</name><name sortKey="Li, Juo Yan" sort="Li, Juo Yan" uniqKey="Li J" first="Juo Yan" last="Li">Juo Yan Li</name></noCountry><country name="Taïwan"><noRegion><name sortKey="Wu, Cheng Guo" sort="Wu, Cheng Guo" uniqKey="Wu C" first="Cheng Guo" last="Wu">Cheng Guo Wu</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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