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 (acetylcholinebinding protein). The complex buries ∼2000 A2 (1 A=0.1 nm) of surface area, within which Arg36 and Phe 32 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 interresidue interactions diverge from those in a 4.2Astructure of α-ctx (α-cobratoxin) bound to AChBP, but are similar to those in a 1.94 A 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.
Original language | English (US) |
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Pages (from-to) | 303-310 |
Number of pages | 8 |
Journal | Biochemical Journal |
Volume | 454 |
Issue number | 2 |
DOIs | |
State | Published - Sep 1 2013 |
Keywords
- Crystal structure
- Molecular recognition
- Neurotoxin
- Nicotinic acetylcholine receptor
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology