Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like aza-peptide epoxide.
Identifieur interne : 004875 ( Main/Curation ); précédent : 004874; suivant : 004876Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like aza-peptide epoxide.
Auteurs : Ting-Wai Lee [Canada] ; Maia M. Cherney ; Carly Huitema ; Jie Liu ; Karen Ellis James ; James C. Powers ; Lindsay D. Eltis ; Michael N G. JamesSource :
- Journal of molecular biology [ 0022-2836 ] ; 2005.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Cysteine Endopeptidases, Epoxy Compounds, Peptides, Protease Inhibitors.
- chemistry : SARS Virus.
- Binding Sites, Catalysis, Crystallography, X-Ray, Hydrogen-Ion Concentration, Molecular Structure.
Abstract
The main peptidase (M(pro)) from the coronavirus (CoV) causing severe acute respiratory syndrome (SARS) is one of the most attractive molecular targets for the development of anti-SARS agents. We report the irreversible inhibition of SARS-CoV M(pro) by an aza-peptide epoxide (APE; k(inact)/K(i) = 1900(+/-400) M(-1) s(-1)). The crystal structures of the M(pro):APE complex in the space groups C2 and P2(1)2(1)2(1) revealed the formation of a covalent bond between the catalytic Cys145 S(gamma) atom of the peptidase and the epoxide C3 atom of the inhibitor, substantiating the mode of action of this class of cysteine-peptidase inhibitors. The aza-peptide component of APE binds in the substrate-binding regions of M(pro) in a substrate-like manner, with excellent structural and chemical complementarity. In addition, the crystal structure of unbound M(pro) in the space group C2 revealed that the "N-fingers" (N-terminal residues 1 to 7) of both protomers of M(pro) are well defined and the substrate-binding regions of both protomers are in the catalytically competent conformation at the crystallization pH of 6.5, contrary to the previously determined crystal structures of unbound M(pro) in the space group P2(1).
DOI: 10.1016/j.jmb.2005.09.004
PubMed: 16219322
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pubmed:16219322Le document en format XML
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Cherney</name></author><author><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name></author><author><name sortKey="Liu, Jie" sort="Liu, Jie" uniqKey="Liu J" first="Jie" last="Liu">Jie Liu</name></author><author><name sortKey="James, Karen Ellis" sort="James, Karen Ellis" uniqKey="James K" first="Karen Ellis" last="James">Karen Ellis James</name></author><author><name sortKey="Powers, James C" sort="Powers, James C" uniqKey="Powers J" first="James C" last="Powers">James C. Powers</name></author><author><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name></author><author><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. 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Cherney</name></author><author><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name></author><author><name sortKey="Liu, Jie" sort="Liu, Jie" uniqKey="Liu J" first="Jie" last="Liu">Jie Liu</name></author><author><name sortKey="James, Karen Ellis" sort="James, Karen Ellis" uniqKey="James K" first="Karen Ellis" last="James">Karen Ellis James</name></author><author><name sortKey="Powers, James C" sort="Powers, James C" uniqKey="Powers J" first="James C" last="Powers">James C. Powers</name></author><author><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name></author><author><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. James</name></author></analytic><series><title level="j">Journal of molecular biology</title><idno type="ISSN">0022-2836</idno><imprint><date when="2005" type="published">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites</term><term>Catalysis</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Epoxy Compounds (chemistry)</term><term>Hydrogen-Ion Concentration</term><term>Molecular Structure</term><term>Peptides (chemistry)</term><term>Protease Inhibitors (chemistry)</term><term>SARS Virus (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Catalyse</term><term>Composés époxy ()</term><term>Concentration en ions d'hydrogène</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases ()</term><term>Inhibiteurs de protéases ()</term><term>Peptides ()</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Virus du SRAS ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Epoxy Compounds</term><term>Peptides</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Catalysis</term><term>Crystallography, X-Ray</term><term>Hydrogen-Ion Concentration</term><term>Molecular Structure</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Catalyse</term><term>Composés époxy</term><term>Concentration en ions d'hydrogène</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Inhibiteurs de protéases</term><term>Peptides</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The main peptidase (M(pro)) from the coronavirus (CoV) causing severe acute respiratory syndrome (SARS) is one of the most attractive molecular targets for the development of anti-SARS agents. We report the irreversible inhibition of SARS-CoV M(pro) by an aza-peptide epoxide (APE; k(inact)/K(i) = 1900(+/-400) M(-1) s(-1)). The crystal structures of the M(pro):APE complex in the space groups C2 and P2(1)2(1)2(1) revealed the formation of a covalent bond between the catalytic Cys145 S(gamma) atom of the peptidase and the epoxide C3 atom of the inhibitor, substantiating the mode of action of this class of cysteine-peptidase inhibitors. The aza-peptide component of APE binds in the substrate-binding regions of M(pro) in a substrate-like manner, with excellent structural and chemical complementarity. In addition, the crystal structure of unbound M(pro) in the space group C2 revealed that the "N-fingers" (N-terminal residues 1 to 7) of both protomers of M(pro) are well defined and the substrate-binding regions of both protomers are in the catalytically competent conformation at the crystallization pH of 6.5, contrary to the previously determined crystal structures of unbound M(pro) in the space group P2(1).</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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