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题名: GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches
作者: Pang, Xue-qin1;  Liu, Jian-yong1
关键词: A(2A) adenosine receptor ;  Molecular dynamics ;  Adenosine ;  Specific binding ;  Conformational dynamics ;  Ionic lock ;  Rotamer toggle switch ;  Secondary structure
刊名: CHINESE JOURNAL OF CHEMICAL PHYSICS
发表日期: 2014-02-01
DOI: 10.1063/1674-0068/27/01/29-38
卷: 27, 期:1, 页:29-38
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Physics, Atomic, Molecular & Chemical
研究领域[WOS]: Physics
英文摘要: Agonist binding of A(2A) adenosine receptor (A(2A)AR) shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing A(2A)AR selectively binding agonists. Using molecular dynamics (MD) simulations, we have studied the interactions between A(2A)AR and its agonist (adenosine), and analyzed the induced dynamic behaviors of the receptor. Key residues interacting with adenosine are identified: A63(2.61), 166(2.64), V84(3.32), L85(3.33), T88(3.36), F168(5.29), M177(5.38), L249(6.51), H250(6.52), and N253(6.55) interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L167(5.28) is observed, which supports our previous findings that L167(5.28) is an antagonist specific binding reside. The dynamic behaviors of agonist bound A(2A)AR are found to be different from apo-A(2A)AR in three typical functional switches: (i) tight "ionic lock" forms in adenosine-A(2A)AR, but it is in equilibrium between formation and breakage in apo-A(2A)AR; (ii) the "rotamer toggle switch", T88(3.36)/F242(6.44)/W246(6.48), adopted different rotameric conformations in adenosine-A(2A)AR and apo-A(2A)AR; (iii) adenosine-A(2A)AR has a flexible intracellular loop 2 (IC2) and alpha-helical IC3, while apo-A(2A)AR preferred alpha-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic functional switches in adenosine-A(2A)AR and apo-A(2A)AR.
关键词[WOS]: PROTEIN-COUPLED RECEPTOR ;  BETA-ADRENERGIC-RECEPTORS ;  ADENOSINE RECEPTOR ;  MOLECULAR-DYNAMICS ;  CRYSTAL-STRUCTURE ;  TRANSMEMBRANE HELICES ;  MUSCARINIC RECEPTOR ;  INTRACELLULAR LOOP ;  ACTIVATION ;  RHODOPSIN
语种: 英语
WOS记录号: WOS:000332921500006
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/145447
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China

Recommended Citation:
Pang, Xue-qin,Liu, Jian-yong. GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches[J]. CHINESE JOURNAL OF CHEMICAL PHYSICS,2014,27(1):29-38.
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