Publication

Structural 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., 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 journalArticleAcademicpeer-review

  • Divya Kesters
  • Andrew J Thompson
  • Marijke Brams
  • René van Elk
  • Radovan Spurny
  • Matthis Geitmann
  • Jose M Villalgordo
  • Albert Guskov
  • U Helena Danielson
  • Sarah C R Lummis
  • August B Smit
  • Chris Ulens

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.

Original languageEnglish
Pages (from-to)49-56
Number of pages8
JournalEmbo Reports
Volume14
Issue number1
Publication statusPublished - Jan-2013
Externally publishedYes

    Keywords

  • 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

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