2YME

Crystal structure of a mutant binding protein (5HTBP-AChBP) in complex with granisetron

Summary for 2YME

• Entry DOI: 10.2210/pdb2yme/pdb
• Related: 2YMD
• Descriptor: SOLUBLE ACETYLCHOLINE RECEPTOR, 2-acetamido-2-deoxy-beta-D-glucopyranose, 1-methyl-N-[(1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]indazole-3-carboxamide, ... (6 entities in total)
• Functional Keywords: receptor, pentameric ligand-gated ion channel
• Biological source: APLYSIA CALIFORNICA (CALIFORNIA SEA HARE)
• Total number of polymer chains: 10
• Total formula weight: 239044.18

Authors

Kesters, D.,Thompson, A.J.,Brams, M.,Elk, R.v.,Spurny, R.,Geitmann, M.,Villalgordo, J.M.,Guskov, A.,Danielson, U.H.,Lummis, S.C.R.,Smit, A.B.,Ulens, C. (deposition date: 2012-10-09, release date: 2012-12-26, Last modification date: 2024-11-20)

Primary citation

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.
Structural Basis of Ligand Recognition in 5-Ht3 Receptors.
Embo Rep., 14:49-, 2013

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-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.

PubMed: 23196367
DOI: 10.1038/EMBOR.2012.189

Experimental method

X-RAY DIFFRACTION (2.4 Å)