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Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors.
- Source :
-
Nature communications [Nat Commun] 2015 Aug 18; Vol. 6, pp. 8057. Date of Electronic Publication: 2015 Aug 18. - Publication Year :
- 2015
-
Abstract
- α-Bungarotoxin (α-Btx) binds to the five agonist binding sites on the homopentameric α7-acetylcholine receptor, yet the number of bound α-Btx molecules required to prevent agonist-induced channel opening remains unknown. To determine the stoichiometry for α-Btx blockade, we generate receptors comprised of wild-type and α-Btx-resistant subunits, tag one of the subunit types with conductance mutations to report subunit stoichiometry, and following incubation with α-Btx, monitor opening of individual receptor channels with defined subunit stoichiometry. We find that a single α-Btx-sensitive subunit confers nearly maximal suppression of channel opening, despite four binding sites remaining unoccupied by α-Btx and accessible to the agonist. Given structural evidence that α-Btx locks the agonist binding site in an inactive conformation, we conclude that the dominant mechanism of antagonism is non-competitive, originating from conformational arrest of the binding sites, and that the five α7 subunits are interdependent and maintain conformational symmetry in the open channel state.
- Subjects :
- Binding Sites
Gene Expression Regulation drug effects
HEK293 Cells
Humans
Iodine Radioisotopes
Kinetics
Models, Molecular
Mutagenesis, Site-Directed
Mutation
Protein Binding
Protein Conformation
alpha7 Nicotinic Acetylcholine Receptor genetics
alpha7 Nicotinic Acetylcholine Receptor metabolism
Bungarotoxins pharmacology
alpha7 Nicotinic Acetylcholine Receptor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 26282895
- Full Text :
- https://doi.org/10.1038/ncomms9057