A G_q/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 Gα_i signaling in vivo (1, 2). Also, Gα_s-coupled G protein-coupled receptors have been engineered to generate Gα_s-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 Gα_q/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.