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GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches
Pang, Xue-qin; Liu, Jian-yong
Keyworda(2a) Adenosine Receptor Molecular Dynamics Adenosine Specific Binding Conformational Dynamics Ionic Lock Rotamer Toggle Switch Secondary Structure
Source PublicationCHINESE JOURNAL OF CHEMICAL PHYSICS
2014-02-01
DOI10.1063/1674-0068/27/01/29-38
Volume27Issue:1Pages:29-38
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Physical Sciences
WOS SubjectPhysics, Atomic, Molecular & Chemical
WOS Research AreaPhysics
WOS KeywordPROTEIN-COUPLED RECEPTOR ; BETA-ADRENERGIC-RECEPTORS ; ADENOSINE RECEPTOR ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; TRANSMEMBRANE HELICES ; MUSCARINIC RECEPTOR ; INTRACELLULAR LOOP ; ACTIVATION ; RHODOPSIN
AbstractAgonist 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.
Language英语
WOS IDWOS:000332921500006
Citation statistics
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/145447
Collection中国科学院大连化学物理研究所
AffiliationChinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
Recommended Citation
GB/T 7714
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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