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Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera.
- Source :
-
The Biochemical journal [Biochem J] 2013 Sep 01; Vol. 454 (2), pp. 303-310. - Publication Year :
- 2013
-
Abstract
- To identify high-affinity interactions between long-chain α-neurotoxins and nicotinic receptors, we determined the crystal structure of the complex between α-btx (α-bungarotoxin) and a pentameric ligand-binding domain constructed from the human α7 AChR (acetylcholine receptor) and AChBP (acetylcholine-binding protein). The complex buries ~2000 Ų (1 Å=0.1 nm) of surface area, within which Arg³⁶ and Phe³² from finger II of α-btx form a π-cation stack that aligns edge-to-face with the conserved Tyr¹⁸⁴ from loop-C of α7, while Asp³⁰ of α-btx forms a hydrogen bond with the hydroxy group of Tyr¹⁸⁴. These inter-residue interactions diverge from those in a 4.2 Å structure of α-ctx (α-cobratoxin) bound to AChBP, but are similar to those in a 1.94 Å structure of α-btx bound to the monomeric α1 extracellular domain, although compared with the monomer-bound complex, the α-btx backbone exhibits a large shift relative to the protein surface. Mutational analyses show that replacing Tyr¹⁸⁴ with a threonine residue abolishes high-affinity α-btx binding, whereas replacing with a phenylalanine residue maintains high affinity. Comparison of the α-btx complex with that coupled to the agonist epibatidine reveals structural rearrangements within the binding pocket and throughout each subunit. The overall findings highlight structural principles by which α-neurotoxins interact with nicotinic receptors.
- Subjects :
- Amino Acid Substitution
Animals
Binding Sites
Bridged Bicyclo Compounds, Heterocyclic chemistry
Bridged Bicyclo Compounds, Heterocyclic metabolism
Bungarotoxins chemistry
Bungarus
Carrier Proteins chemistry
Carrier Proteins genetics
Cobra Neurotoxin Proteins chemistry
Cobra Neurotoxin Proteins metabolism
Humans
Ligands
Lymnaea
Mutant Proteins chemistry
Mutant Proteins metabolism
Neurotoxins chemistry
Nicotinic Agonists chemistry
Nicotinic Agonists metabolism
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
Protein Conformation
Protein Interaction Domains and Motifs
Pyridines chemistry
Pyridines metabolism
Receptors, Nicotinic chemistry
Receptors, Nicotinic genetics
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins metabolism
Reptilian Proteins chemistry
alpha7 Nicotinic Acetylcholine Receptor
Bungarotoxins metabolism
Carrier Proteins metabolism
Models, Molecular
Neurotoxins metabolism
Receptors, Nicotinic metabolism
Reptilian Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 454
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 23800261
- Full Text :
- https://doi.org/10.1042/BJ20130636