Structural basis of ligand recognition in 5-HT3 receptors
2013 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 14, no 1, 49-56 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2013. Vol. 14, no 1, 49-56 p.
5-hydroxytryptamine-3 receptor, Cys-loop receptor, pentameric ligand-gated ion channel, serotonin
IdentifiersURN: urn:nbn:se:uu:diva-195065DOI: 10.1038/embor.2012.189ISI: 000316980300014OAI: oai:DiVA.org:uu-195065DiVA: diva2:606814