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J. Virol. doi:10.1128/JVI.02680-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mechanism for Controlling Dimer-monomer Switch and Coupling Dimerization to Catalysis of the SARS-CoV 3C-Like Protease

Department of Biological Sciences, Faculty of Science, Department of Biochemistry, Yong Loo Lin School of Medicine and National University of Singapore; 10 Kent Ridge Crescent, Singapore 119260

^* To whom correspondence should be addressed. Email: dbsjayar{at}nus.edu.sg. bchsj{at}nus.edu.sg.

	Abstract

Unlike 3C protease, the SARS-CoV 3C-like protease (3CLpro) is only enzymatically active as a homodimer and its catalysis is under extensive regulation by the unique extra domain. Despite intense studies, two puzzles still remain: 1) how dimer-monomer switch is controlled; and 2) why dimerization is absolutely required for catalysis. Here we report the monomeric crystal structure of the SARS-CoV 3CLpro mutant R298A at a resolution of 1.75 Å. Detailed analysis reveals that Arg298 serves as a key component for maintaining dimerization and consequently its mutation will trigger a cooperative switch from dimer to monomer. The monomeric enzyme is irreversibly inactivated because its catalytic machinery is frozen in the collapsed state, characteristic of the formation of a short 3₁₀-helix from an active-site loop. Remarkably, dimerization appears to be coupled to catalysis in 3CLpro through use of overlapped residues for two networks, one for dimerization and another for the catalysis.