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

• Published in: The Journal of biological chemistry 2006-05, Vol.281 (20), p.13894-13898
• Main Authors: Chen, Hao, Wei, Ping, Huang, Changkang, Tan, Lei, Liu, Ying, Lai, Luhua
• Format: Article
• Language: English
• Subjects: Binding Sites; Catalysis; Colorimetry; Coronavirus 3C Proteases; Crystallization; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - physiology; Dimerization; Endopeptidases - chemistry; Enzyme Catalysis and Regulation; Glutamic Acid - chemistry; Hydrogen Bonding; Kinetics; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Protein Subunits - chemistry; SARS coronavirus; SARS Virus - enzymology; Substrate Specificity; Viral Proteins - chemistry; Viral Proteins - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M510745200

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.