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-Å 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.