Structural basis of ligand recognition in 5-HT3 receptorsKesters, D., Thompson, A. J., Brams, M., van Elk, R., Spurny, R., Geitmann, M., Villalgordo, J. M., Guskov, A., Danielson, U. H., Lummis, S. C. R., Smit, A. B. & Ulens, C., Jan-2013, In : Embo Reports. 14, 1, p. 49-56 8 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||8|
|Publication status||Published - Jan-2013|
- Amino Acid Sequence, Antiemetics, Binding Sites, Crystallography, X-Ray, Granisetron, Humans, Hydrophobic and Hydrophilic Interactions, Kinetics, Ligands, Models, Molecular, Molecular Sequence Data, Protein Engineering, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Subunits, Receptors, Serotonin, 5-HT3, Recombinant Proteins, Sequence Alignment, Serotonin, Serotonin Receptor Agonists, Static Electricity, Thermodynamics