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Prediction of 5-HT₃ Receptor Agonist-Binding Residues Using Homology Modeling

Department of Biochemistry, University of Cambridge, Cambridge CB2 1AG, United Kingdom

Correspondence: Address reprint requests to Sarah C. R. Lummis, Dept. of Biochemistry, University of Cambridge, Tennis Court Rd., Cambridge CB2 1AG, UK. Tel.: +44-1223-765950; Fax: +44-1223-333345; E-mail: sl120{at}cam.ac.uk.

5-HT₃ receptors demonstrate significant structural and functional homology to other members of the Cys-loop ligand-gated ion channel superfamily. The extracellular domains of these receptors share similar sequence homology (20%) with Limnaea acetylcholine binding protein, for which an x-ray crystal structure is available. We used this structure as a template for computer-based homology modeling of the 5-HT₃ receptor extracellular domain. AutoDock software was used to dock 5-HT into the putative 5-HT₃ receptor ligand-binding site, resulting in seven alternative energetically favorable models. Residues located no more than 5 Å from the docked 5-HT were identified for each model; of these, 12 were found to be common to all seven models with five others present in only certain models. Some docking models reflected the cation- interaction previously demonstrated for W183, and data from these and other studies were used to define our preferred models.

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