Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1 beta: One Microsecond Molecular Dynamics Simulations
文献类型：期刊论文
| 作者 | Du, Yun; Yang, Huaiyu; Xu, Yechun ; Cang, Xiaohui; Luo, Cheng; Mao, Yanyan; Wang, Yuanyuan; Qin, Guangrong; Luo, Xiaomin; Jiang, Hualiang
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| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
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| 出版日期 | 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. |
| 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 |
| 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研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000302887300035 |
| 出版者 | AMER CHEMICAL SOC |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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