title: pH-dependent conformational flexibility of the SARS-CoV main proteinase (M(pro)) dimer: molecular dynamics simulations and multiple X-ray structure analyses.
abstract: 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.
authors.affiliation: 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
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Tan
authors.forename: Koen H G
authors.initials: KH
authors.lastname: Verschueren
authors.forename: Kanchan
authors.initials: K
authors.lastname: Anand
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Maojun
authors.initials: M
authors.lastname: Yang
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
authors.forename: Janna
authors.initials: J
authors.lastname: Bigalke
authors.forename: Burkhard
authors.initials: B
authors.lastname: Heisen
authors.forename: Jeroen R
authors.initials: JR
authors.lastname: Mesters
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Rolf
authors.initials: R
authors.lastname: Hilgenfeld
mesh_terms: 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*
chemical_list: D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases