Paper Citing NAMD - Abstract
Pang, Xueqin; Yang, Mingjun; Han, Keli
Antagonist binding and induced conformational dynamics of GPCR A(2A) adenosine receptor
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 81:1399-1410, AUG 2013
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.
