title: A G(q/11)-coupled mutant histamine H(1) 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 Galpha(i) signaling in vivo (1, 2). Also, Galpha(s)-coupled G protein-coupled receptors have been engineered to generate Galpha(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 Galpha(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.
authors: Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
authors: Martijn
authors: M
authors: Bruysters
authors: Aldo
authors: A
authors: Jongejan
authors: Atilla
authors: A
authors: Akdemir
authors: Remko A
authors: RA
authors: Bakker
authors: Rob
authors: R
authors: Leurs
mesh_terms: D000818:Animals; D019556:COS Cells; D002417:Cattle; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry* / Q000235:genetics*; D017930:Genes, Reporter; D006632:Histamine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry; D011485:Protein Binding; D015202:Protein Engineering; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000737:chemistry*; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D008024:Ligands; D016328:NF-kappa B; D011969:Receptors, Histamine H1; D017473:Receptors, Opioid, kappa; C110260:Ro1 protein, synthetic; D010649:Phenylalanine; D006632:Histamine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11