Only one monomer is active in the dimer of SARS 3C-like proteinase

doi:10.1074/jbc.M510745200

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Papers In Press, published online ahead of print March 24, 2006
J. Biol. Chem, 10.1074/jbc.M510745200
Submitted on October 3, 2005
Revised on March 8, 2006
Accepted on March 24, 2006

Only one monomer is active in the dimer of SARS 3C-like proteinase

Hao Chen, Ping Wei, Changkang Huang, Lei Tan, Ying Liu, and Luhua Lai

College of Chemistry, Peking University, Beijing 100871

Corresponding Author: lhlai{at}pku.edu.cn

The severe acute respiratory syndrome coronavirus 3C-like protease has been proposed to be a key target for structural 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 investigate the problems why only the dimer is active and whether both of the two protomers in the dimer are active by using molecular dynamics simulation and mutational studies. The molecular dynamics simulations show that the monomers are always inactive and the two protomers in the dimer are asymmetric and 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 association activation catalysis dissociation mechanism for activity control.

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