Ligand binding effects on the activation of the EGFR extracellular domain
文献类型：期刊论文
| 作者 | Shao, Qiang2,3 ; Zhu, Weiliang1,2,3
|
| 刊名 | PHYSICAL CHEMISTRY CHEMICAL PHYSICS
 |
| 出版日期 | 2019-04-21 |
| 卷号 | 21期号:15页码:8141-8151 |
| ISSN号 | 1463-9076 |
| DOI | 10.1039/c8cp07496h |
| 通讯作者 | Shao, Qiang(qshao@simm.ac.cn) |
| 英文摘要 | The epidermal growth factor receptor (EGFR) is one of the most common target proteins in anti-cancer therapy. The binding of the EGF ligand to the EGFR extracellular domain (EGFR-ECD) promotes its inactive-to-active conformational transition (activation) but the relevant detailed mechanism remains elusive still. Here, the structural characterization and energetics of the EGFR-ECD conformational transition with and without the binding of the EGF are quantitatively explored using an innovative enhanced sampling MD simulation method. Intriguingly, the EGF offers hydrophobic interactions (e.g., EGF residues of Tyr44 and Leu47) and electrostatic interactions (e.g., the EGF residues of Glu5, Asp11, Asp17, and Arg41) to play a dominant role in dragging domain III to close the ligand binding domain gap. Subsequently, the correlation between domains III and II is enhanced through salt-bridges among Glu376, Arg403, and Arg405 from domain III and Glu293, Glu295, and Arg300 from domain II. Finally, the structural bending of domain II is regulated to facilitate the disengagement of domain II from domain IV. In this regard, the functional conformational transition of EGFR-ECD is a consequence of the cooperative motion of protein domains driven by the EGF ligand binding. The present study shows a detailed scenario of the EGF induced activation of EGFR-ECD and provides valuable information for drug discovery targeting the EGFR. |
| WOS关键词 | EPIDERMAL-GROWTH-FACTOR ; NORMAL-MODE ANALYSIS ; FACTOR RECEPTOR ; MOLECULAR-DYNAMICS ; ENERGY LANDSCAPE ; CONFORMATIONAL TRANSITION ; CRYSTAL-STRUCTURE ; MEMBRANE ; PATHWAYS ; SIMULATIONS |
| 资助项目 | National Key Research and Development Program[2016YFA0502301] ; National Natural Science Foundation of China[21373258] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) |
| WOS研究方向 | Chemistry ; Physics |
| 语种 | 英语 |
| 出版者 | ROYAL SOC CHEMISTRY |
| WOS记录号 | WOS:000465260400043 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/289913]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shao, Qiang |
| 作者单位 | 1.Pilot Natl Lab Marine Sci & Technol, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shao, Qiang,Zhu, Weiliang. Ligand binding effects on the activation of the EGFR extracellular domain[J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS,2019,21(15):8141-8151. |
| APA | Shao, Qiang,&Zhu, Weiliang.(2019).Ligand binding effects on the activation of the EGFR extracellular domain.PHYSICAL CHEMISTRY CHEMICAL PHYSICS,21(15),8141-8151. |
| MLA | Shao, Qiang,et al."Ligand binding effects on the activation of the EGFR extracellular domain".PHYSICAL CHEMISTRY CHEMICAL PHYSICS 21.15(2019):8141-8151. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。