SARS-CoV 3C-like protease (3CLpro) is an attractive target for
anti- severe acute respiratory syndrome (SARS) drug discovery,
and its dimerization has been extensively proved to be indispensable
for enzymatic activity. However, the reason why the dissociated
monomer is inactive still remains unclear due to the absence of the
monomer structure. In this study, we showed that mutation of
the dimer-interface residue Gly-11 to alanine entirely abolished
theactivityofSARS-CoV3CLpro.Subsequently,wedeterminedthe
crystal structure of this mutant and discovered a complete crystallographic
dimer dissociation of SARS-CoV 3CLpro. The mutation
might shorten the-helixA of domain I and cause a mis-oriented
N-terminal finger that could not correctly squeeze into the pocket
of another monomer during dimerization, thus destabilizing the
dimer structure. Several structural features essential for catalysis
and substrate recognition are severely impaired in the G11A monomer.
Moreover, domain III rotates dramatically against the chymotrypsin
fold compared with the dimer, from which we proposed
a putative dimerization model for SARS-CoV 3CLpro. As the first
reported monomer structure for SARS-CoV 3CLpro, the crystal
structure ofG11Amutant might provide insight into the dimerization
mechanism of the protease and supply direct structural evidence
for the incompetence of the dissociated monomer.