Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 127, Issue 1, Pages 350-356Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja0461771
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- NINDS NIH HHS [NS34407, NS11756] Funding Source: Medline
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The binding of three distinct agonists-acetylcholine (ACh), nicotine, and epibatidine-to the nicotinic acetylcholine receptor has been probed using unnatural amino acid mutagenesis. ACh makes a cation-pi interaction with Trp alpha 49, while nicotine employs a hydrogen bond to a backbone carbonyl in the same region of the agonist binding site. The nicotine analogue epibatidine achieves its high potency by taking advantage of both the cation-pi interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp alpha 49 suggests that a novel aromatic C-H (...) O=C hydrogen bond further augments the binding of epibatidine. These studies illustrate the subtleties and complexities of the interactions between drugs and membrane receptors and establish a paradigm for obtaining detailed structural information.
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