Download MendeleyStructural Basis of Ligand Recognition in 5-Ht(3) Receptors.
Kesters, D., Thompson, A.J., Brams, M., Van Elk, R., Spurny, R., Geitmann, M., Villalgordo, J.M., Guskov, A., Helena Danielson, U., Lummis, S.C., Smit, A.B., Ulens, C.(2013) EMBO Rep 14: 49
- PubMed: 23196367
- DOI: https://doi.org/10.1038/embor.2012.189
- Primary Citation of Related Structures:
2YMD, 2YME - PubMed 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-¦Ð 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.
Organizational Affiliation:
Laboratory of Structural Neurobiology, KULeuven, Leuven, Belgium.
