Mechanism for the Autophosphorylation of CheA Histidine Kinase: QM/MM Calculations

doi:10.1021/jp203968d

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Mechanism for the Autophosphorylation of CheA Histidine Kinase: QM/MM Calculations
	Shi, Ting 2,3; Lu, Yunxiang 1; Liu, Xinyi 2; Chen, Yingyi 2; Jiang, Hualiang3 ; Zhang, Jian 2
刊名	JOURNAL OF PHYSICAL CHEMISTRY B
	2011-10-20
卷号	115 期号:41 页码:11895-11901
ISSN号	1520-6106
DOI	10.1021/jp203968d
文献子类	Article
英文摘要	The CheA histidine ldnase, a model of TCS (the two-component system), mediates the signal transduction pathway of bacterial chemotaxis via autophosphorylation. Since the TCSs are rarely found in mammalians, they have become attractive targets for the development of new antibiotics. To characterize the autophosphoryl-transfer mechanism of CheA histidine ldnase, molecular dynamics simulations combined with quantum mechanics/molecular mechanics calculations were employed on the constructed 3D model of PI-P4-ATP complex. A two-step reaction mechanism was proposed and confirmed by our computations: the autophosphoryl-transfer reaction takes place followed by a rapid and reversible conformational change from ground state to prechemistry state. In addition, a two-dimensional potential energy surface was calculated for autophosphorylation, and the transition state displays an associative character. Moreover, we found Lys48 serves as the catalytic acid to stabilize transition state through a water-mediated proton-transfer pathway, and Glu67 acts as not only a hydrogen bond acceptor but also a structure anchor to modulate the imidazole ring of His45 in the active site. Our findings clearly provide a detailed autophosphoryl-transfer mechanism of CheA histidine kinase and thus are important for discovering new antibiotics.
资助项目	National Basic Research Program of China (973 Program)[2011CB504001] ; National Natural Science Foundation of China[21002062] ; Innovative Research Team of Shanghai Municipal Education Commission[00000000] ; Shanghai Institutions of Higher Learning[00000000] ; Shanghai PuJiang Program[10PJ406800]
WOS关键词	2-COMPONENT SIGNAL-TRANSDUCTION ; ACTIVE-SITE ; BACTERIAL CHEMOTAXIS ; THERMOTOGA-MARITIMA ; ATP BINDING ; PROTEINS ; PHOSPHORYLATION ; DOMAIN ; ONIOM ; INHIBITORS
WOS研究方向	Chemistry
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000295700700016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278370]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhang, Jian
作者单位	1.E China Univ Sci & Technol, Dept Chem, Shanghai 200237, Peoples R China; 2.Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol,Minist Educ, Key Lab Cell Differentiat & Apoptosis Chinese, Shanghai 200025, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Shi, Ting,Lu, Yunxiang,Liu, Xinyi,et al. Mechanism for the Autophosphorylation of CheA Histidine Kinase: QM/MM Calculations[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2011,115(41):11895-11901.
APA	Shi, Ting,Lu, Yunxiang,Liu, Xinyi,Chen, Yingyi,Jiang, Hualiang,&Zhang, Jian.(2011).Mechanism for the Autophosphorylation of CheA Histidine Kinase: QM/MM Calculations.JOURNAL OF PHYSICAL CHEMISTRY B,115(41),11895-11901.
MLA	Shi, Ting,et al."Mechanism for the Autophosphorylation of CheA Histidine Kinase: QM/MM Calculations".JOURNAL OF PHYSICAL CHEMISTRY B 115.41(2011):11895-11901.