Structural basis of ligand recognition in 5-HT(3) receptors

D. Kesters, A.J. Thompson, M. Brams, R. van Elk, R. Spurny, M. Geitmann, J.M. Villalgordo, A. Guskov, U.H. Danielson, S.C.R. Lummis, A.B. Smit, C. Ulens

Research output: Contribution to JournalArticleAcademicpeer-review


The 5-HT 3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT 3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT 3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT 3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT 3 receptor. © 2013 European Molecular Biology Organization.
Original languageEnglish
Pages (from-to)49-56
JournalEMBO Reports
Publication statusPublished - 2013


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