View : 20 Download: 0

Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor

Title
Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor
Authors
Kim S.-K.Gao Z.-G.Jeong L.S.Jacobson K.A.
Ewha Authors
정낙신
Issue Date
2006
Journal Title
Journal of Molecular Graphics and Modelling
ISSN
1093-3263JCR Link
Citation
vol. 25, no. 4, pp. 562 - 577
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Structural determinants of ligand efficacy in the human A3 adenosine receptor (AR) were studied using pharmacophore and docking analyses of various categories of A3 selective ligands: inverse agonist, neutral antagonist (nonnucleoside and nucleoside), and agonist (partial and full). The homology modeling of GPCRs was adapted to provide two templates: the rhodopsin-based resting state for antagonist binding and a putative Meta I state, conformationally altered at a key residue (W6.48), for agonist binding. The preferential binding domains and/or local conformational changes associated with docking of three high affinity A3AR ligands were compared: inverse agonist PSB-11 1 ((R)-8-ethyl-4-methyl-2-phenyl-imidazo[2,1-i]purin-5-one); neutral antagonist MRE-3008F20 7 (5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)pyra-zolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine), and full agonist Cl-IB-MECA 21 (2-chloro-N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine) to define a distinct recognition mode for each. Ribose-containing agonists were more hydrophilic than nonnucleoside antagonists, and H-bonding ability at the ribose 3′- and 5′-positions was required for agonism. From the receptor perspective, common requirements for activation included the destabilization of H-bond networks at W6.48 and H7.43, the specific interactions of the ribose moiety in its putative hydrophilic pocket at T3.36, S7.42, and H7.43, the stabilization of the complex by inward movement of F5.43, and the characteristic rotation of W6.48. By analogy, outward rotation of the W6.48 side-chain upon activation of an internally-crosslinking mutant M3 muscarinic receptor was indicated by constrained molecular dynamics (MD). Our results are consistent with an anti-clockwise rotation (from the extracellular view) of transmembrane domains 3, 5, 6, and 7, as proposed for other Family A GPCRs. Thus, the putative conformational changes associated with A3AR activation indicate a shared mechanism of GPCR activation similar to rhodopsin. © 2006 Elsevier Inc. All rights reserved.
DOI
10.1016/j.jmgm.2006.05.004
Appears in Collections:
약학대학 > 약학과 > Journal papers
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE