Download MendeleyStructural Basis of Ligand Recognition in 5-Ht3 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.R., 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.
