Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme.
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-A 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.
Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, IL 60607, USA.
Kiira
K
Ratia
Kumar Singh
KS
Saikatendu
Bernard D
BD
Santarsiero
Naina
N
Barretto
Susan C
SC
Baker
Raymond C
RC
Stevens
Andrew D
AD
Mesecar
D001665:Binding Sites; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D010206:Papain / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D017433:Protein Structure, Secondary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D025801:Ubiquitin / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry*
D025801:Ubiquitin; D014764:Viral Proteins; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D010206:Papain; D000086782:Coronavirus 3C Proteases