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Analysis of full and partial agonists binding to β 2 ‐adrenergic receptor suggests a role of transmembrane helix V in agonist‐specific conformational changes
Author(s) -
Katritch Vsevolod,
Reynolds Kimberly A.,
Cherezov Vadim,
Hanson Michael A.,
Roth Christopher B.,
Yeager Mark,
Abagyan Ruben
Publication year - 2009
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.949
Subject(s) - inverse agonist , agonist , g protein coupled receptor , partial agonist , chemistry , helix (gastropod) , receptor , ligand (biochemistry) , functional selectivity , stereochemistry , steric effects , transmembrane domain , biophysics , biochemistry , biology , ecology , snail
The 2.4 Å crystal structure of the β 2 ‐adrenergic receptor ( β 2 AR) in complex with the high‐affinity inverse agonist (−)‐carazolol provides a detailed structural framework for the analysis of ligand recognition by adrenergic receptors. Insights into agonist binding and the corresponding conformational changes triggering G‐protein coupled receptor (GPCR) activation mechanism are of special interest. Here we show that while the carazolol pocket captured in the β 2 AR crystal structure accommodates (−)‐isoproterenol and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM‐V helix (TM‐Ve) obtained by receptor optimization in the presence of docked ligand can further improve the calculated binding affinities for agonist compounds. Tilting of TM‐Ve towards the receptor axis provides a more complete description of polar receptor–ligand interactions for full and partial agonists, by enabling optimal engagement of agonists with two experimentally identified anchor sites, formed by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Further, receptor models incorporating a flexible TM‐V backbone allow reliable prediction of binding affinities for a set of diverse ligands, suggesting potential utility of this approach to design of effective and subtype‐specific agonists for adrenergic receptors. Systematic differences in capacity of partial, full and inverse agonists to induce TM‐V helix tilt in the β 2 AR model suggest potential role of TM‐V as a conformational “rheostat” involved in the whole spectrum of β 2 AR responses to small molecule signals. Copyright © 2009 John Wiley & Sons, Ltd.