Antagonist binding and induced conformational dynamics of GPCR A2A adenosine receptor. Issue 8 (2nd July 2013)

• Record Type: Journal Article
• Authors: Pang, Xueqin; Yang, Mingjun; Han, Keli
• Is Part Of: Proteins. Volume 81:Issue 8(2013)
• Page Start: 1399
• Page End: 1410
• Publication Date: 2013-07-02
• Subjects: A2AAR -- molecular dynamics -- ZM241385 -- KW6002 -- ligand specific binding -- ionic lock -- rotamer toggle switch -- secondary structure; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.24283
• Languages: English
• ISSNs: 0887-3585

Abstract

Abstract : The A2A adenosine receptor (A2A AR) is a unique G‐protein coupled receptor (GPCR), because besides agonist, its antagonist could also lead to therapeutic relevance. Based on A2A AR‐antagonist crystal structure, we have studied the binding mechanism of two distinct antagonists, ZM241385 and KW6002, and dynamic behaviors of A2A 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‐A2A ARs were found to be different from the apo‐A2A AR in three typical functional switches, (i) the "ionic lock" was in equilibrium between formation and breakage in apo‐A2A AR, but stayed broken in holo‐A2A ARs; (ii) the "rotamer toggle switch, " T88 3.36 /F242 6.44 /W246 6.48, adopted different rotameric conformations in apo‐A2A AR and holo‐A2A ARs; (iii) apo‐A2A AR preferred α‐helical intracellular loop (IC)2 and flexible IC3, while holo‐A2A ARs had a flexible IC2 and α‐helical IC3. Our results indicated that antagonist binding induced different conformational rearrangements of these characteristic functional switches in apo‐A2A AR and holo‐A2A ARs. Proteins 2013; 81:1399–1410. © 2013 Wiley Periodicals, Inc.