Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity.
Identifieur interne : 001237 ( Main/Exploration ); précédent : 001236; suivant : 001238Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity.
Auteurs : Danielle Needle [États-Unis] ; George T. Lountos [États-Unis] ; David S. Waugh [États-Unis]Source :
- Acta crystallographica. Section D, Biological crystallography [ 1399-0047 ] ; 2015.
Descripteurs français
- KwdFr :
- Antienzymes (pharmacologie), Antiviraux (pharmacologie), Conformation des protéines, Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie), Cristallographie aux rayons X, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Domaine catalytique, Données de séquences moléculaires, Humains, Modèles moléculaires, Similitude de séquences d'acides aminés, Spécificité du substrat, Séquence d'acides aminés.
- MESH :
- enzymologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- métabolisme : Cysteine endopeptidases.
- pharmacologie : Antienzymes, Antiviraux.
- Conformation des protéines, Cristallographie aux rayons X, Cysteine endopeptidases, Domaine catalytique, Données de séquences moléculaires, Humains, Modèles moléculaires, Similitude de séquences d'acides aminés, Spécificité du substrat, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Sequence, Antiviral Agents (pharmacology), Catalytic Domain, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Enzyme Inhibitors (pharmacology), Humans, Middle East Respiratory Syndrome Coronavirus (enzymology), Models, Molecular, Molecular Sequence Data, Protein Conformation, Sequence Homology, Amino Acid, Substrate Specificity.
- MESH :
- chemical , chemistry : Cysteine Endopeptidases.
- chemical , metabolism : Cysteine Endopeptidases.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors.
- enzymology : Middle East Respiratory Syndrome Coronavirus.
- Amino Acid Sequence, Catalytic Domain, Crystallography, X-Ray, Humans, Models, Molecular, Molecular Sequence Data, Protein Conformation, Sequence Homology, Amino Acid, Substrate Specificity.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus that causes severe respiratory illness accompanied by multi-organ dysfunction, resulting in a case fatality rate of approximately 40%. As found in other coronaviruses, the majority of the positive-stranded RNA MERS-CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain-like protease and at 11 sites by a 3C-like protease (3 CL(pro)). Since 3 CL(pro) is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3 CL(pro) inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS-CoV 3 CL(pro) enzyme were determined. The aim was to co-crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C-terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme-product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS-CoV 3 CL(pro); however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure-based design of small-molecule inhibitors of the MERS-CoV 3 CL(pro) enzyme.
DOI: 10.1107/S1399004715003521
PubMed: 25945576
Affiliations:
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Lountos</name><affiliation wicri:level="2"><nlm:affiliation>Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Waugh, David S" sort="Waugh, David S" uniqKey="Waugh D" first="David S" last="Waugh">David S. 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As found in other coronaviruses, the majority of the positive-stranded RNA MERS-CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain-like protease and at 11 sites by a 3C-like protease (3 CL(pro)). Since 3 CL(pro) is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3 CL(pro) inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS-CoV 3 CL(pro) enzyme were determined. The aim was to co-crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C-terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme-product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS-CoV 3 CL(pro); however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure-based design of small-molecule inhibitors of the MERS-CoV 3 CL(pro) enzyme.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Needle, Danielle" sort="Needle, Danielle" uniqKey="Needle D" first="Danielle" last="Needle">Danielle Needle</name></region><name sortKey="Lountos, George T" sort="Lountos, George T" uniqKey="Lountos G" first="George T" last="Lountos">George T. Lountos</name><name sortKey="Waugh, David S" sort="Waugh, David S" uniqKey="Waugh D" first="David S" last="Waugh">David S. Waugh</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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