Palonosetron-5-HT3 Receptor Interactions As Shown by a Binding Protein Cocrystal Structure.
Palonosetron is a potent 5-HT3 receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition in the receptor binding site by obtaining a high resolution structure of palonosetron bound to an engineered acetylcholine binding protein that mimics the 5-HT3 receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT3 receptors with mutated binding site residues. The structural data indicate that palonosetron forms a tight and effective wedge in the binding pocket, made possible by its rigid tricyclic ring structure and its interactions with binding site residues; it adopts a binding pose that is distinct from the related antiemetics granisetron and tropisetron. The functional data show many residues previously shown to interact with agonists and antagonists in the binding site are important for palonosetron binding, and indicate those of particular importance are W183 (a cation-π interaction and a hydrogen bond) and Y153 (a hydrogen bond). This information, and the availability of the structure of palonosetron bound to 5-HTBP, should aid the development of novel and more efficacious drugs that act via 5-HT3 receptors.
['Price|Kerry L|KL|', 'Lillestol|Reidun K|RK|', 'Ulens|Chris|C|', 'Lummis|Sarah C R|SC|']
D000818:Animals D001048:Aplysia D001665:Binding Sites D002352:Carrier Proteins D018360:Crystallography, X-Ray D004305:Dose-Response Relationship, Drug D057809:HEK293 Cells D006801:Humans D006860:Hydrogen Bonding D057927:Hydrophobic and Hydrophilic Interactions D007546:Isoquinolines D008564:Membrane Potentials D008958:Models, Molecular D015394:Molecular Structure D009154:Mutation D000077924:Palonosetron D015202:Protein Engineering D011812:Quinuclidines D044406:Receptors, Serotonin, 5-HT3 D058831:Serotonin 5-HT3 Receptor Antagonists
Cys-loop receptor Ligand-gated ion channel serotonin receptor