RT Journal Article
SR Electronic
T1 Conformation of Ligands Bound to the Muscarinic Acetylcholine Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 778
OP 787
DO 10.1124/mol.62.4.778
VO 62
IS 4
A1 Hiroyasu Furukawa
A1 Toshiyuki Hamada
A1 Mariko K. Hayashi
A1 Tatsuya Haga
A1 Yutaka Muto
A1 Hiroshi Hirota
A1 Shigeyuki Yokoyama
A1 Kazuo Nagasawa
A1 Masaji Ishiguro
YR 2002
UL http://molpharm.aspetjournals.org/content/62/4/778.abstract
AB 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 M2mAChR-(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.