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J. Biol. Chem., Vol. 281, Issue 20, 13894-13898, May 19, 2006

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Only One Protomer Is Active in the Dimer of SARS 3C-like Proteinase^*

Hao Chen¹, Ping Wei¹, Changkang Huang, Lei Tan, Ying Liu, and Luhua Lai²

From the State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry, Peking University, Beijing 100871, China and Center for Theoretical Biology, Peking University, Beijing 100871, China

The severe acute respiratory syndrome coronavirus 3C-like protease has been proposed to be a key target for structurally based drug design against SARS. The enzyme exists as a mixture of dimer and monomer, and only the dimer was considered to be active. In this report, we have investigated, using molecular dynamics simulation and mutational studies, the problems as to why only the dimer is active and whether both of the two protomers in the dimer are active. The molecular dynamics simulations show that the monomers are always inactive, that the two protomers in the dimer are asymmetric, and that only one protomer is active at a time. The enzyme activity of the hybrid severe acute respiratory syndrome coronavirus 3C-like protease of the wild-type protein and the inactive mutant proves that the dimerization is important for enzyme activity and only one active protomer in the dimer is enough for the catalysis. Our simulations also show that the right conformation for catalysis in one protomer can be induced upon dimer formation. These results suggest that the enzyme may follow the association, activation, catalysis, and dissociation mechanism for activity control.

Received for publication, October 3, 2005 , and in revised form, March 8, 2006.

^* This work was supported in part by the Ministry of Science and Technology of China and National Natural Science Foundation of China (20473001, 90403001, 30490245, 20228306). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables SI and SII.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Tel.: 86-10-62757486; Fax. 86-10-62751725; E-mail: lhlai{at}pku.edu.cn.

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