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Title: Structural basis of ligand recognition in 5-HT3 receptors
Authors: Thompson, Andrew J.
Villalgordo, Jose M.
Lummis, Sarah C. R.
Smit, August B.
Kesters, Divya
Elk, René van
Brams, Marijke
Spurny, Radovan
Geitmann, Matthis
Guskov, Albert
Danielson, U. Helena
Ulens, Chris
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2013
Source: Kesters, D., Thompson, A. J., Brams, M., Elk, R. v., Spurny, R., Geitmann, M., et al. (2013). Structural basis of ligand recognition in 5-HT3 receptors. EMBO Reports, 14(1), 49-56.
Series/Report no.: EMBO reports
Abstract: The 5-HT3 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-HT3 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-HT3 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-HT3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT3 receptor.
ISSN: 1469-221X
DOI: 10.1038/embor.2012.189
Schools: School of Biological Sciences 
Rights: © 2013 European Molecular Biology Organization. This paper was published in EMBO Reports and is made available as an electronic reprint (preprint) with permission of European Molecular Biology Organization. The paper can be found at the following official DOI: []. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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