title: Binding interactions of antagonists with 5-hydroxytryptamine3A receptor models.
abstract: Homology modeling was performed on the N-terminal extracellular regions of human, mouse, and guinea pig 5-hydroxytryptamine type 3A receptors (5-HT3R) based on the 24% sequence homology with and on the crystal structure of the snail acetylcholine binding protein (AChBP). Docking of 5-HT3 antagonists granisetron, tropisetron, ondansetron, dolasetron ('setrons), and (+)-tubocurarine suggests an aromatic binding cleft behind a hydrophilic vestibule. Several intra- and interface interactions, H-bonds, and salt bridges stabilize the pentameric structure and the binding cleft. The planar rings of antagonists are intercalated between aromatic side-chains (W183-Y234, Y143-Y153). S227 donates H-bonds to the carbonyl groups of 'setrons. The tertiary ammonium ions interact with E236, N128 or E129, and/or W90 (cation-pi interaction). This offers a molecular explanation of the pharmacophore models of 5-HT3R antagonists. Docking artifacts suggest some ambiguities in the binding loops A and C of the 5-HT3AR models. Lower potencies of (+)-tubocurarine for human, and those of tropisetron for guinea pig 5-HT3ARs can be attributed to steric differences of I/S230 in the binding cleft and to distinct binding interactions with E229 and S227, respectively. Ligand binding interferes with crucial intra- and interface interactions along the binding cleft.
authors: Department of Molecular Pharmacology, Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Gábor
authors: G
authors: Maksay
authors: Zsolt
authors: Z
authors: Bikádi
authors: Miklós
authors: M
authors: Simonyi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D021122:Protein Subunits; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D021122:Protein Subunits; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists