pH-dependent conformational flexibility of the SARS-CoV main proteinase (M(pro)) dimer: molecular dynamics simulations and multiple X-ray structure analyses.
The SARS coronavirus main proteinase (M(pro)) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the M(pro) by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the M(pro) monomer and the need for dimerization are also discussed.
Tan
Jinzhi
J
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Verschueren
Koen H G
KH
Anand
Kanchan
K
Shen
Jianhua
J
Yang
Maojun
M
Xu
Yechun
Y
Rao
Zihe
Z
Bigalke
Janna
J
Heisen
Burkhard
B
Mesters
Jeroen R
JR
Chen
Kaixian
K
Shen
Xu
X
Jiang
Hualiang
H
Hilgenfeld
Rolf
R
D001665:Binding Sites; D003198:Computer Simulation; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D019281:Dimerization; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D011487:Protein Conformation; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*
D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases