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

Recently, G protein-coupled receptors activated solely by synthetic ligands (RASSLs) have been introduced as new tools to study G alpha(i) signaling in vivo ( 1, 2). Also, G alpha(s)-coupled G protein-coupled receptors have been engineered to generate G alpha(s)-coupled RASSLs ( 3, 4). In this study, we exploited the differences in binding pockets between different classes of H-1 receptor agonists and identified the first G alpha(q/11)-coupled RASSL. The mutant human H-1 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.