The SARS coronavirus main peptidase (SARS-CoV Mpro) plays an essential role in the life-cycle of the virus and is a primary target for the development of anti-SARS agents. Here, we report the crystal structure of Mpro at a resolution of 1.82 Å, in space group P21 at pH 6.0. In contrast to the previously reported structure of Mpro in the same space group at the same pH, the active sites and the S1 specificity pockets of both protomers in the structure of Mpro reported here are in the catalytically competent conformation, suggesting their conformational flexibility. We report two crystal structures of Mpro having an additional Ala at the N terminus of each protomer (M+A(-1)pro), both at a resolution of 2.00 Å, in space group P43212: one unbound and one bound by a substrate-like aza-peptide epoxide (APE). In the unbound form, the active sites and the S1 specificity pockets of both protomers of M+A(-1)pro are observed in a collapsed (catalytically incompetent) conformation; whereas they are in an open (catalytically competent) conformation in the APE-bound form. The observed conformational flexibility of the active sites and the S1 specificity pockets suggests that these parts of Mpro exist in dynamic equilibrium. The structural data further suggest that the binding of APE to Mpro follows an induced-fit model. The substrate likely also binds in an induced-fit manner in a process that may help drive the catalytic cycle. © 2006 Elsevier Ltd.
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