Mapping the Functional Binding Sites of Cholesterol in beta(2)-Adrenergic Receptor by Long-Time Molecular Dynamics Simulations
文献类型：期刊论文
| 作者 | Cang, Xiaohui; Du, Yun; Mao, Yanyan; Wang, Yuanyuan; Yang, Huaiyu; Jiang, Hualiang
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| 刊名 | JOURNAL OF PHYSICAL CHEMISTRY B
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| 出版日期 | 2013-01-31 |
| 卷号 | 117期号:4页码:1085-1094 |
| ISSN号 | 1520-6106 |
| DOI | 10.1021/jp3118192 |
| 文献子类 | Article |
| 英文摘要 | Cholesterol, an abundant membrane component in both lipid rafts and caveolae of cell membrane, plays a crucial role in regulating the function and organization of various G-protein coupled receptors (GPCRs). However, the underlying mechanism for cholesterol-GPCR interaction is still unclear. To this end, we performed a series of microsecond molecular dynamics (MD) simulations on beta(2)-adrenergic receptor (beta(2)AR) in the presence and absence of cholesterol molecules in the POPC bilayer. The unbiased MD simulation on the system with cholesterols reveals that cholesterol molecules can spontaneously diffuse to seven sites on the beta(2)AR surfaces, three in the extracellular leaflet (e1-e3) and four in the intracellular leaflet (i1, i2, i4, and i5). The MD simulation identifies three cholesterol-binding sites (i2, e2, and e3) that are also observed in the crystal structures of several GPCRs. Cholesterol binding to site e1 lock Trp313(7.40) into a certain conformation that may facilitate ligand-receptor binding, and cholesterol binding to site i2 provides a structural support for the reported cholesterol-mediate dimeric form of beta(2)AR (PDB code 2RH1). In addition, both competitive and cooperative effects between cholesterols and phospholipids in binding to beta(2)AR were observed in our MD simulations. Together, these results provide new insights into cholesterol-GPCR interactions. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; A(2A) ADENOSINE RECEPTOR ; CRYSTAL-STRUCTURE ; MEMBRANE CHOLESTEROL ; ADRENERGIC-RECEPTOR ; BETA(2) ADRENOCEPTOR ; SIGNAL-TRANSDUCTION ; CARDIAC MYOCYTES ; STRUCTURAL BASIS ; WATER MODELS |
| 资助项目 | State Key Program of Basic Research of China[2012CB518005] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[31100594] ; Shanghai Science and Technology Development Funds[12QA1404000] ; Shanghai Science and Technology Development Funds[11ZR1444400] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000314492300013 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277759]  |
| 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, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cang, Xiaohui,Du, Yun,Mao, Yanyan,et al. Mapping the Functional Binding Sites of Cholesterol in beta(2)-Adrenergic Receptor by Long-Time Molecular Dynamics Simulations[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2013,117(4):1085-1094. |
| APA | Cang, Xiaohui,Du, Yun,Mao, Yanyan,Wang, Yuanyuan,Yang, Huaiyu,&Jiang, Hualiang.(2013).Mapping the Functional Binding Sites of Cholesterol in beta(2)-Adrenergic Receptor by Long-Time Molecular Dynamics Simulations.JOURNAL OF PHYSICAL CHEMISTRY B,117(4),1085-1094. |
| MLA | Cang, Xiaohui,et al."Mapping the Functional Binding Sites of Cholesterol in beta(2)-Adrenergic Receptor by Long-Time Molecular Dynamics Simulations".JOURNAL OF PHYSICAL CHEMISTRY B 117.4(2013):1085-1094. |
入库方式： OAI收割
来源：上海药物研究所
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