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题名: Antagonist binding and induced conformational dynamics of GPCR A(2A) adenosine receptor
作者: Pang, Xueqin1;  Yang, Mingjun1;  Han, Keli1
关键词: A(2A)AR ;  molecular dynamics ;  ZM241385 ;  KW6002 ;  ligand specific binding ;  ionic lock ;  rotamer toggle switch ;  secondary structure
刊名: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
发表日期: 2013-08-01
DOI: 10.1002/prot.24283
卷: 81, 期:8, 页:1399-1410
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology ;  Biophysics
研究领域[WOS]: Biochemistry & Molecular Biology ;  Biophysics
英文摘要: The A(2A) adenosine receptor (A(2A)AR) is a unique G-protein coupled receptor (GPCR), because besides agonist, its antagonist could also lead to therapeutic relevance. Based on A(2A)AR-antagonist crystal structure, we have studied the binding mechanism of two distinct antagonists, ZM241385 and KW6002, and dynamic behaviors of A(2A)AR induced by antagonist binding. Key residues interacting with both antagonists and residues specifically binding to one of them are identified. ZM241385 specifically bound to S67(2.65), M177(5.38), and N253(6.55), while KW6002 binds to F62(2.60), A81(3.29), and H264(7.29). Moreover, interactions with L167(5.28) are found for both antagonists, which were not reported in agonist binding. The dynamic behaviors of antagonist bound holo-A(2A)ARs were found to be different from the apo-A(2A)AR in three typical functional switches, (i) the ionic lock was in equilibrium between formation and breakage in apo-A(2A)AR, but stayed broken in holo-A(2A)ARs; (ii) the rotamer toggle switch, T88(3.36)/F242(6.44)/W246(6.48), adopted different rotameric conformations in apo-A(2A)AR and holo-A(2A)ARs; (iii) apo-A(2A)AR preferred -helical intracellular loop (IC)2 and flexible IC3, while holo-A(2A)ARs had a flexible IC2 and -helical IC3. Our results indicated that antagonist binding induced different conformational rearrangements of these characteristic functional switches in apo-A(2A)AR and holo-A(2A)ARs. Proteins 2013; 81:1399-1410. (c) 2013 Wiley Periodicals, Inc.
关键词[WOS]: PROTEIN-COUPLED RECEPTOR ;  ANGSTROM CRYSTAL-STRUCTURE ;  MOLECULAR-DYNAMICS ;  TRANSMEMBRANE HELICES ;  MUSCARINIC RECEPTOR ;  PARKINSONS-DISEASE ;  INTRACELLULAR LOOP ;  RHODOPSIN ;  ACTIVATION ;  DOPAMINE
语种: 英语
WOS记录号: WOS:000329220400010
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137928
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, Liaoning, Peoples R China

Recommended Citation:
Pang, Xueqin,Yang, Mingjun,Han, Keli. Antagonist binding and induced conformational dynamics of GPCR A(2A) adenosine receptor[J]. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS,2013,81(8):1399-1410.
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