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GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches
Pang, Xue-qin; Liu, Jian-yong
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
2014-02-01
DOI10.1063/1674-0068/27/01/29-38
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
关键词[WOS]PROTEIN-COUPLED RECEPTOR ; BETA-ADRENERGIC-RECEPTORS ; ADENOSINE RECEPTOR ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; TRANSMEMBRANE HELICES ; MUSCARINIC RECEPTOR ; INTRACELLULAR LOOP ; ACTIVATION ; RHODOPSIN
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.
语种英语
WOS记录号WOS:000332921500006
引用统计
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/145447
专题中国科学院大连化学物理研究所
作者单位Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
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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.
APA Pang, Xue-qin,&Liu, Jian-yong.(2014).GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches.CHINESE JOURNAL OF CHEMICAL PHYSICS,27(1),29-38.
MLA Pang, Xue-qin,et al."GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches".CHINESE JOURNAL OF CHEMICAL PHYSICS 27.1(2014):29-38.
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