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First published on October 20, 2004; DOI: 10.1124/mol.104.003665

0026-895X/05/6701-123-131$20.00
Mol Pharmacol 67:123-131, 2005

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Structural Basis for Epibatidine Selectivity at Desensitized Nicotinic Receptors

Richard A. Pennington, Fan Gao, Steven M. Sine, and Richard J. Prince

School of Biological Sciences, University of Manchester, Manchester, United Kingdom (R.A.P., R.J.P.); and Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota (F.G., S.M.S.)

The agonist binding sites of the fetal muscle nicotinic acetylcholine receptor are formed at the interfaces of {alpha}-subunits and neighboring {gamma}- and {delta}-subunits. When the receptor is in the nonconducting desensitized state, the {alpha}-{gamma} site binds the agonist epibatidine 200-fold more tightly than does the {alpha}-{delta} site. To determine the structural basis for this selectivity, we constructed {gamma}/{delta}-subunit chimeras, coexpressed them with complementary wild-type subunits in HEK 293 cells, and determined epibatidine affinity of the resulting complexes. The results reveal three determinants of epibatidine selectivity: {gamma}104–117/{delta}106–{delta}119, {gamma}164–171/{delta}166–177, and {gamma}Pro190/{delta}Ala196. Point mutations reveal that three sequence differences within the {gamma}104–117/{delta}106–{delta}119 region are determinants of epibatidine selectivity: {gamma}Lys104/{delta}Tyr106, {gamma}Ser111/{delta}Tyr113, and {gamma}Tyr117/{delta}Tyr119. In the {delta}-subunit, simultaneous mutation of these residues to their {gamma} equivalent produces high affinity, {gamma}-like epibatidine binding. However, converting {gamma} to {delta} affinity requires replacement of the {gamma}104–117 segment with {delta} sequence, suggesting interplay of residues in this region. The structural basis for epibatidine selectivity is explained by computational docking of epibatidine to a homology model of the {alpha}-{gamma} binding site.

Received June 7, 2004; accepted October 19, 2004

Address correspondence to: Dr. Richard J. Prince, School of Biological Sciences, University of Manchester, G38 Stopford Bldg., Oxford Rd, Manchester M13 9PT, United Kingdom. E-mail: richard.prince{at}man.ac.uk






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