期刊
EMBO REPORTS
卷 14, 期 1, 页码 49-56出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/embor.2012.189
关键词
Cys-loop receptor; pentameric ligand-gated ion channel; serotonin; 5-hydroxytryptamine-3 receptor
资金
- European Union [HEALTH-F2-2007-202088]
- Wellcome Trust
- [KULeuven OT/08/048]
- [FWO G.0939.11N]
- [G.0743.10N]
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-p 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.
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