Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors.
Inhibition of the 5-hydroxytryptamine receptor (5-HT(3)R), a member of the Cys-loop superfamily of Ligand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. With respect to the many other drugs already in use, such as the first generation 5-HT(3)R antagonist granisetron, palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potency towards the 5-HT(3)Rs. Five different receptor monomers, the 5-HT(3)R A-E, have been identified although the A and B subunits are the only known to build functional receptors, the homopentameric 5-HT(3A)R and the heteropentameric 5-HT(3B-A)R (with BBABA subunit arrangement). At present, however, no three-dimensional structure has been reported for any of the 5-HT(3)R subunits. To understand the binding properties of agonists and antagonists, models of the extracellular portion of the 5-HT(3)R A and B subunits are built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of the known three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results of docking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron into the modelled homomeric and heteromeric 5-HT(3)R binding interfaces, provide a possible rationalization both of the higher potency of palonosetron with respect to other antagonists, and of its previously reported allosteric binding and positive cooperativity properties.
Moura Barbosa
Arménio J
AJ
Department of Chemistry, University of Modena and Reggio Emilia, Via G. Campi 183, 41100 Modena, Italy.
De Rienzo
Francesca
F
Ramos
Maria J
MJ
Menziani
Maria Cristina
MC
D000595:Amino Acid Sequence; D001665:Binding Sites; D019281:Dimerization; D017829:Granisetron / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism
D017829:Granisetron; D008024:Ligands; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D012702:Serotonin Antagonists