Structural basis for epibatidine selectivity at desensitized nicotinic receptors

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The agonist binding sites of the fetal muscle nicotinic acetylcholine receptor are formed at the interfaces of α-subunits and neighboring γ- and δ-subunits. When the receptor is in the nonconducting desensitized state, the α-γ site binds the agonist epibatidine 200-fold more tightly than does the α-δ site. To determine the structural basis for this selectivity, we constructed γ/δ-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: γ104-117/δ106-δ119, γ164-171/δ166-177, and γPro190/δAla196. Point mutations reveal that three sequence differences within the γ104-117/δ106-δ119 region are determinants of epibatidine selectivity: γLys104/δTyr106, γSer111/ δTyr113, and γTyr117/δTyr119. In the δ-subunit, simultaneous mutation of these residues to their γ equivalent produces high affinity, γ-like epibatidine binding. However, converting γ to δ affinity requires replacement of the γ104-117 segment with δ 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 α-γ binding site.

Original languageEnglish (US)
Pages (from-to)123-131
Number of pages9
JournalMolecular pharmacology
Volume67
Issue number1
DOIs
StatePublished - Jan 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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