Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 15, Pages 5717-5722Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0510851103
Keywords
membrane-associated protease; ubiquitin-like domain
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Funding
- NCI NIH HHS [Y1-CO-1020] Funding Source: Medline
- NIAID NIH HHS [P01 AI060915, AI266200400058C] Funding Source: Medline
- NIGMS NIH HHS [Y1-GM-1104] Funding Source: Medline
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Replication of severe acute respiratory syndrome (SARS) Coronavirus (SARS-CoV) requires proteolytic processing of the replicase polyprotein by two viral cysteine proteases, a chymotrypsin-like protease (3CLpro) and a papain-like protease (PLpro). These proteases are important targets for development of antiviral drugs that would inhibit viral replication and reduce mortality associated with outbreaks of SARS-CoV. In this work, we describe the 1.85-angstrom crystal structure of the catalytic core of SARS-CoV PLpro and show that the overall architecture adopts a fold closely resembling that of known deubiquitinating enzymes. Key features, however, distinguish PLpro from characterized deubiquitinating enzymes, including an intact zinc-binding motif, an unobstructed catalytically competent active site, and the presence of an intriguing, ubiquitin-like N-terminal domain. To gain insight into the active-site recognition of the C-terminal tail of ubiquitin and the related LXGG motif, we propose a model of PLpro in complex with ubiquitin-aldehyde that reveals well defined sites within the catalytic cleft that help to account for strict substrate-recognition motifs.
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