Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1 beta: One Microsecond Molecular Dynamics Simulations

doi:10.1021/ja211941d

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	Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1 beta: One Microsecond Molecular Dynamics Simulations
	Du, Yun; Yang, Huaiyu; Xu, Yechun; Cang, Xiaohui; Luo, Cheng; Mao, Yanyan; Wang, Yuanyuan; Qin, Guangrong; Luo, Xiaomin; Jiang, Hualiang
刊名	JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
	2012-04-18
卷号	134 期号:15 页码:6720-6731
ISSN号	0002-7863
DOI	10.1021/ja211941d
文献子类	Article
英文摘要	ErbB4, a receptor tyrosine kinase of the ErbB family, plays crucial roles in cell growth and differentiation, especially in the development of the heart and nervous system. Ligand binding to its extracellular region could modulate the activation process. To understand the mechanism of ErbB4 activation induced by ligand binding, we performed one microsecond molecular dynamics (MD) simulations on the ErbB4 extracellular region (ECR) with and without its endogenous ligand neuregulin1 beta (NRG1 beta). The conformational transition of the ECR-ErbB4/NRG1 beta complex from a tethered inactive conformation to an extended active-like form has been observed, while such large and function-related conformational change has not been seen in the simulation on the ECR-ErbB4, suggesting that ligand binding is indeed the active inducing force for the conformational transition and further dimerization. On the basis of MD simulations and principal component analysis, we constructed a rough energy landscape for the conformational transition of ECR-ErbB4/NRG1 beta complex, suggesting that the conformational change from the inactive state to active-like state involves a stable conformation. The energy barrier for the tether opening was estimated as similar to 2.7 kcal/mol, which is very close to the experimental value (1-2 kcal/mol) reported for ErbB1. On the basis of the simulation results, an atomic mechanism for the ligand-induced activation of ErbB4 was postulated. The present MD simulations provide a new insight into the conformational changes underlying the activation of ErbB4.
资助项目	State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[20721003] ; National Natural Science Foundation of China[20720102040] ; National ST Major Project[2009ZX09501-001] ; CAS[00000000]
WOS关键词	EPIDERMAL-GROWTH-FACTOR ; RECEPTOR EXTRACELLULAR DOMAINS ; TYROSINE KINASE INHIBITOR ; POSITIVE BREAST-CANCER ; PARTICLE MESH EWALD ; AMBER FORCE-FIELD ; ESTROGEN-RECEPTOR ; SIGNALING NETWORK ; CRYSTAL-STRUCTURE ; COLONY FORMATION
WOS研究方向	Chemistry
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000302887300035
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278115]
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	Yang, Huaiyu
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Du, Yun,Yang, Huaiyu,Xu, Yechun,et al. Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1 beta: One Microsecond Molecular Dynamics Simulations[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2012,134(15):6720-6731.
APA	Du, Yun.,Yang, Huaiyu.,Xu, Yechun.,Cang, Xiaohui.,Luo, Cheng.,...&Jiang, Hualiang.(2012).Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1 beta: One Microsecond Molecular Dynamics Simulations.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,134(15),6720-6731.
MLA	Du, Yun,et al."Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1 beta: One Microsecond Molecular Dynamics Simulations".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 134.15(2012):6720-6731.