Binding Interactions of Antagonists with 5-Hydroxytryptamine3A Receptor Models

G. Maksay, Zsolt Bikádi, M. Simonyi

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Homology modeling was performed on the N-terminal extracellular regions of human, mouse, and guinea pig 5-hydroxytryptamine type 3A receptors (5-HT 3R) based on the 24% sequence homology with and on the crystal structure of the snail acetylcholine binding protein (AChBP). Docking of 5-HT3 antagonists granisetron, tropisetron, ondansetron, dolasetron ('setrons), and (+)-tubocurarine suggests an aromatic binding cleft behind a hydrophilic vestibule. Several intra- and interface interactions, H-bonds, and salt bridges stabilize the pentameric structure and the binding cleft. The planar rings of antagonists are intercalated between aromatic side-chains (W183-Y234, Y143-Y153). S227 donates H-bonds to the carbonyl groups of 'setrons. The tertiary ammonium ions interact with E236, N128 or E129, and/or W90 (cation-π interaction). This offers a molecular explanation of the pharmacophore models of 5-HT3R antagonists. Docking artifacts suggest some ambiguities in the binding loops A and C of the 5-HT3AR models. Lower potencies of (+)-tubocurarine for human, and those of tropisetron for guinea pig 5-HT3ARs can be attributed to steric differences of I/S230 in the binding cleft and to distinct binding interactions with E229 and S227, respectively. Ligand binding interferes with crucial intra- and interface interactions along the binding cleft.

Original languageEnglish
Pages (from-to)255-270
Number of pages16
JournalJournal of Receptors and Signal Transduction
Volume23
Issue number2-3
DOIs
Publication statusPublished - 2003

Fingerprint

tropisetron
Tubocurarine
Guinea Pigs
Granisetron
Serotonin 5-HT3 Receptor Antagonists
Ondansetron
Serotonin Receptors
Sequence Homology
Ammonium Compounds
Artifacts
Cations
Serotonin
Salts
Crystal structure
Ions
Ligands

Keywords

  • 5-HT receptor
  • Docking of antagonists
  • Homology modeling
  • Pharmacophore model
  • Species differences
  • Tropisetron
  • Tubocurarine

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Binding Interactions of Antagonists with 5-Hydroxytryptamine3A Receptor Models. / Maksay, G.; Bikádi, Zsolt; Simonyi, M.

In: Journal of Receptors and Signal Transduction, Vol. 23, No. 2-3, 2003, p. 255-270.

Research output: Contribution to journalArticle

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