Conformation of ligands bound to the muscarinic acetylcholine receptor

Furukawa, H., Hamada, T., Hayashi, M. K., Haga, T., Muto, Y., Hirota, H., Yokoyama, S., Nagasawa, K., Ishiguro, M. (October 2002) Conformation of ligands bound to the muscarinic acetylcholine receptor. Mol Pharmacol, 62 (4). pp. 778-87. ISSN 0026-895X (Print)0026-895X (Linking)

DOI: 10.1124/mol.62.4.778


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 M(2) muscarinic acetylcholine receptor (M(2) 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 degrees. This is distinct from the predominant conformations of these ligands in solution with O-C2-C1-N dihedral angle (+80 to approximately 85 degrees ) in the absence of the M(2) mAChR, as assessed by analyses of the coupling constants and nuclear Overhauser effect spectroscopy. We have also built a molecular model of the M(2) 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 degrees, 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 M(2) mAChR in the absence of G protein.

Item Type: Paper
Uncontrolled Keywords: Animals Binding Sites Cells Cultured GTP Binding Proteins metabolism Insects Methacholine Chloride chemistry metabolism Models Molecular Molecular Conformation Muscarine chemistry metabolism Muscarinic Agonists chemistry metabolism Mutation Receptor Muscarinic M2 Receptors Muscarinic chemistry genetics metabolism Structure Activity Relationship
Subjects: Investigative techniques and equipment > spectroscopy > magnetic resonance spectroscopy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein receptor
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Leigh Johnson
Date: October 2002
Date Deposited: 06 Mar 2012 19:11
Last Modified: 05 Jan 2017 22:12
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