Title: Structural basis of ligand recognition in 5-HT(3) receptors
Authors: Kesters, Divya ×
Thompson, Andrew J
Brams, Marijke
van Elk, René
Spurny, Radovan
Geitmann, Matthis
Villalgordo, Jose M
Guskov, Albert
Helena Danielson, U
Lummis, Sarah C R
Smit, August B
Ulens, Chris #
Issue Date: Jan-2013
Publisher: Published for EMBO by Oxford University Press
Series Title: EMBO Reports vol:14 issue:1 pages:49-56
Article number: 10.1038/embor.2012.189
Abstract: 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.
ISSN: 1469-221X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Structural Neurobiology
× corresponding author
# (joint) last author

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