Mutation of Gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3C-like protease - Crystal structure with molecular dynamics simulations

	Mutation of Gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3C-like protease - Crystal structure with molecular dynamics simulations
	Chen, S; Hu, T; Zhang, J; Chen, J; Chen, K; Ding, J; Jiang, H; Shen, X
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2008
卷号	283 期号:1 页码:554-564
通讯作者	Jiang, H (reprint author), Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.,hljiang@mail.shcnc.ac.cn ; xshen@mail.shcnc.ac.cn
英文摘要	SARS-CoV 3C-like protease (3CL(pro)) is an attractive target for anti-severe acute respiratory syndrome (SARS) drug discovery, and its dimerization has been extensively proved to be indispensable for enzymatic activity. However, the reason why the dissociated monomer is inactive still remains unclear due to the absence of the monomer structure. In this study, we showed that mutation of the dimer-interface residue Gly-11 to alanine entirely abolished the activity of SARS-CoV 3CL(pro). Subsequently, we determined the crystal structure of this mutant and discovered a complete crystallographic dimer dissociation of SARS-CoV 3CL(pro). The mutation might shorten the alpha-helix A' of domain I and cause a mis-oriented N-terminal finger that could not correctly squeeze into the pocket of another monomer during dimerization, thus destabilizing the dimer structure. Several structural features essential for catalysis and substrate recognition are severely impaired in the G11A monomer. Moreover, domain III rotates dramatically against the chymotrypsin fold compared with the dimer, from which we proposed a putative dimerization model for SARS-CoV 3CL(pro). As the first reported monomer structure for SARS-CoV 3CL(pro), the crystal structure of G11A mutant might provide insight into the dimerization mechanism of the protease and supply direct structural evidence for the incompetence of the dissociated monomer.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	COV MAIN PROTEINASE ; SARS CORONAVIRUS ; SUBSTRATE-SPECIFICITY ; ENZYMATIC-ACTIVITY ; EXTRA DOMAIN ; M-PRO ; DIMERIZATION ; INHIBITOR ; PURIFICATION ; EXPRESSION
收录类别	SCI
语种	英语
WOS记录号	WOS:000251940300060
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1321]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Chen, S,Hu, T,Zhang, J,et al. Mutation of Gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3C-like protease - Crystal structure with molecular dynamics simulations[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(1):554-564.
APA	Chen, S.,Hu, T.,Zhang, J.,Chen, J.,Chen, K.,...&Shen, X.(2008).Mutation of Gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3C-like protease - Crystal structure with molecular dynamics simulations.JOURNAL OF BIOLOGICAL CHEMISTRY,283(1),554-564.
MLA	Chen, S,et al."Mutation of Gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3C-like protease - Crystal structure with molecular dynamics simulations".JOURNAL OF BIOLOGICAL CHEMISTRY 283.1(2008):554-564.