Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 46, Pages 18031-18036Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0704785104
Keywords
magic-angle spinning; membrane proteins; receptor pharmacology; solid-state NMR
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Funding
- NIGMS NIH HHS [GM 58448, P01 GM058448] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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The conformation of the neurotransmitter acetylcholine bound to the fully functional nicotinic acetylcholine receptor embedded in its native membrane environment has been characterized by using frequency-selective recoupling solid-state NMR. Six dipolar couplings among five resolved C-13-labeled atoms of acetylcholine were measured. Bound acetylcholine adopts a bent conformation characterized with a quaternary ammonium-to-carbonyl distance of 5.1 angstrom. In this conformation, and with its orientation constrained to that previously determined by us, the acetylcholine could be docked satisfactorily in the agonist pocket of the agonist-bound, but not the agonist-free, crystal structure of a soluble acetylcholine-binding protein from Lymnaea stagnali. The quaternary ammonium group of the acetylcholine was determined to be within 3.9 A of five aromatic residues and its acetyl group close to residues C187/188 of the principle and residue L112 of the complementary subunit. The observed >C=O chemical shift is consistent with H bonding to the nicotinic acetylcholine receptor residues gamma Y116 and delta T119 that are homologous to L112 in the soluble acetylcholine-binding protein.
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