A Gq/11-coupled mutant histamine H1 receptor F435A activated solely by synthetic ligands (RASSL)

Abstract

Recently, G protein-coupled receptors activated solely by synthetic ligands (RASSLs) have been introduced as new tools to study Gαi signaling in vivo (1, 2). Also, Gαs-coupled G protein-coupled receptors have been engineered to generate Gαs-coupled RASSLs (3,4). In this study, we exploited the differences in binding pockets between different classes of H1 receptor agonists and identified the first Gαq/11-coupled RASSL. The mutant human H1 receptor F435A (6.55) combines a strongly decreased affinity (25-fold) and potency for the endogenous ligand histamine (200-fold) with improved affinities (54-fold) and potencies (2600-fold) for 2-phenylhistamines, a synthetic class of H 1 receptor agonists. Molecular dynamics simulations provided a mechanism for distinct agonist binding to both wild-type and F435A mutant H 1 receptors. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.