title: Ondansetron and granisetron binding orientation in the 5-HT(3) receptor determined by unnatural amino acid mutagenesis.
abstract: The serotonin type 3 receptor (5-HT(3)R) is a ligand-gated ion channel found in the central and peripheral nervous systems. The 5-HT(3)R is a therapeutic target, and the clinically available drugs ondansetron and granisetron inhibit receptor activity. Their inhibitory action is through competitive binding to the native ligand binding site, although the binding orientation of the drugs at the receptor has been a matter of debate. Here we heterologously express mouse 5-HT(3)A receptors in Xenopus oocytes and use unnatural amino acid mutagenesis to establish a cation-π interaction for both ondansetron and granisetron to tryptophan 183 in the ligand binding pocket. This cation-π interaction establishes a binding orientation for both ondansetron and granisetron within the binding pocket.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Noah H
authors.initials: NH
authors.lastname: Duffy
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D017829:Granisetron / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D017294:Ondansetron / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D017354:Point Mutation; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D017829:Granisetron; D017294:Ondansetron; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists