Abstract
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 alpha149, 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 alpha149 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcholine / chemistry
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Acetylcholine / metabolism
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Acetylcholine / pharmacology
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Chemical Phenomena
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Chemistry, Physical
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Cholinergic Agonists / chemistry*
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Cholinergic Agonists / metabolism*
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Cholinergic Agonists / pharmacology
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Crystallography, X-Ray
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Hydrogen Bonding
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Kinetics
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Models, Molecular
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Nicotine / chemistry
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Nicotine / metabolism
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Nicotine / pharmacology
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Nicotinic Agonists / chemistry*
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Nicotinic Agonists / metabolism*
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Nicotinic Agonists / pharmacology
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Pyridines / chemistry
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Pyridines / metabolism
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Pyridines / pharmacology
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Receptors, Nicotinic / chemistry*
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Receptors, Nicotinic / drug effects
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Receptors, Nicotinic / metabolism*
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Static Electricity
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Surface Properties
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Threonine / analogs & derivatives*
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Threonine / chemistry
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Threonine / metabolism
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Tryptophan / chemistry
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Tryptophan / metabolism
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Xenopus laevis
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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Cholinergic Agonists
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Nicotinic Agonists
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Pyridines
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Receptors, Nicotinic
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hydroxythreonine
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Threonine
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Nicotine
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Tryptophan
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epibatidine
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Acetylcholine