MersV1, Main, Exploration, bibRecord, 001951

Structures of the Middle East respiratory syndrome coronavirus 3C‐like protease reveal insights into substrate specificity

Identifieur interne : 001951 ( Main/Exploration ); précédent : 001950; suivant : 001952

Structures of the Middle East respiratory syndrome coronavirus 3C‐like protease reveal insights into substrate specificity

Auteurs : Danielle Needle ; George T. Lountos ; David S. Waugh

Source :

Acta Crystallographica Section D [ 1399-0047 ] ; 2015-05-01.

RBID : ISTEX:0E6D5FE78A59A65714FE3FD83418405FCA2B30D3

Descripteurs français

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 (3CLpro). Since 3CLpro is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3CLpro inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS‐CoV 3CLpro 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 3CLpro; 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 3CLpro enzyme.

Url:

DOI: 10.1107/S1399004715003521

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en">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 (3CLpro). Since 3CLpro is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3CLpro inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS‐CoV 3CLpro 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 3CLpro; 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 3CLpro enzyme.</div>
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Serveur d'exploration MERS

Structures of the Middle East respiratory syndrome coronavirus 3C‐like protease reveal insights into substrate specificity

Structures of the Middle East respiratory syndrome coronavirus 3C‐like protease reveal insights into substrate specificity

Source :

Descripteurs français

English descriptors

Abstract

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