Conformation of ligands bound to the muscarinic acetylcholine receptor

Hiroyasu Furukawa, Toshiyuki Hamada, Mariko K. Hayashi, Tatsuya Haga, Yutaka Muto, Hiroshi Hirota, Shigeyuki Yokoyama, Kazuo Nagasawa, Masaji Ishiguro

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Abstract

Many biogenic amines evoke a variety of physiological responses by acting on G protein-coupled receptors. We have determined the conformation of two acetylcholine analogs, (S)-methacholine and (2S,4R,5S)-muscarine, bound to the M2 muscarinic acetylcholine receptor (M2 mAChR) by NMR spectroscopy. The analysis of the transferred nuclear Overhauser effect indicated that the receptor selectively recognized the conformers of (S)-methacholine and (2S,4R,5S)-muscarine with the gauche O-C2-C1-N dihedral angle at +60°. This is distinct from the predominant conformations of these ligands in solution with O-C2-C1-N dihedral angle (+80∼85°) in the absence of the M2 mAChR, as assessed by analyses of the coupling constants and nuclear Overhauser effect spectroscopy. We have also built a molecular model of the M2 mAChR-(S)-methacholine complex, based on the X-ray crystallographic structure of rhodopsin. This model indicated that the conformation with the gauche O-C2-C1-N dihedral angle at +55.5°, which is similar to the one determined by NMR measurement, is energetically favored in the binding of (S)-methacholine to the receptor. We suggest that this conformation represents the binding of the agonist to the M2 mAChR in the absence of G protein.

Original languageEnglish
Pages (from-to)778-787
Number of pages10
JournalMolecular Pharmacology
Volume62
Issue number4
DOIs
Publication statusPublished - 2002 Oct 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Furukawa, H., Hamada, T., Hayashi, M. K., Haga, T., Muto, Y., Hirota, H., Yokoyama, S., Nagasawa, K., & Ishiguro, M. (2002). Conformation of ligands bound to the muscarinic acetylcholine receptor. Molecular Pharmacology, 62(4), 778-787. https://doi.org/10.1124/mol.62.4.778