PDBsum entry 2ymd

Receptor

PDB id: 2ymd

Contents

Protein chains

(+ 4 more) 212 a.a.

Ligands

SRO ×10

GOL ×14

PO4 ×10

Waters ×2665

References listed in PDB file

Key reference

• Title: Structural basis of ligand recognition in 5-Ht3 receptors.
• Authors: D.Kesters, A.J.Thompson, M.Brams, R.Van elk, R.Spurny, M.Geitmann, J.M.Villalgordo, A.Guskov, U.H.Danielson, S.C.Lummis, A.B.Smit, C.Ulens.
• Ref.: Embo Rep, 2013, 14, 49-56.
• PubMed id: 23196367

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-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.