Palonosetron-5-HT3Receptor Interactions As Shown by a Binding Protein Cocrystal Structure.

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Price, Kerry L 
Lillestol, Reidun K 
Ulens, Chris 
Lummis, Sarah CR 

Palonosetron is a potent 5-HT3receptor 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-HT3receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT3receptors 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-HT3receptors.

Cys-loop receptor, Ligand-gated ion channel, serotonin receptor, Animals, Aplysia, Binding Sites, Carrier Proteins, Crystallography, X-Ray, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Isoquinolines, Membrane Potentials, Models, Molecular, Molecular Structure, Mutation, Protein Engineering, Quinuclidines, Receptors, Serotonin, 5-HT3, Serotonin 5-HT3 Receptor Antagonists
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ACS Chemical Neuroscience
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American Chemical Society
Medical Research Council (MR/L021676/1)
Supported by a grant from the MRC (MR/L02/676) to S.C.R.L.