Structural highlights
Function
Q8WSF8_APLCA
Publication Abstract from PubMed
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-pi 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.
Structural basis of ligand recognition in 5-HT3 receptors.,Kesters D, Thompson AJ, Brams M, van Elk R, Spurny R, Geitmann M, Villalgordo JM, Guskov A, Helena Danielson U, Lummis SC, Smit AB, Ulens C EMBO Rep. 2012 Nov 30. doi: 10.1038/embor.2012.189. PMID:23196367[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kesters D, Thompson AJ, Brams M, van Elk R, Spurny R, Geitmann M, Villalgordo JM, Guskov A, Helena Danielson U, Lummis SC, Smit AB, Ulens C. Structural basis of ligand recognition in 5-HT3 receptors. EMBO Rep. 2012 Nov 30. doi: 10.1038/embor.2012.189. PMID:23196367 doi:http://dx.doi.org/10.1038/embor.2012.189