Only one protomer is active in the dimer of SARS 3C-like proteinase.
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.
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry, Peking University, Beijing 100871, China.
Hao
H
Chen
Ping
P
Wei
Changkang
C
Huang
Lei
L
Tan
Ying
Y
Liu
Luhua
L
Lai
D001665:Binding Sites; D002384:Catalysis; D003124:Colorimetry; D000086782:Coronavirus 3C Proteases; D003460:Crystallization; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000502:physiology*; D019281:Dimerization; D010450:Endopeptidases / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D013379:Substrate Specificity; D014764:Viral Proteins / Q000737:chemistry* / Q000502:physiology*
D021122:Protein Subunits; D014764:Viral Proteins; D018698:Glutamic Acid; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases