Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera

Sun Huang, Shu Xing Li, Nina Bren, Kevin Cheng, Ryan Gomoto, Lin Chen, Steven M Sine

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)303-310
Number of pages8
JournalBiochemical Journal
Volume454
Issue number2
DOIs
StatePublished - Sep 1 2013

Fingerprint

Bungarotoxins
epibatidine
Neurotoxins
Nicotinic Receptors
Ligands
Cholinergic Receptors
Threonine
Phenylalanine
varespladib methyl
Fingers
Cations
Hydrogen
Hydrogen bonds
Membrane Proteins
Proteins
Monomers
Crystal structure

Keywords

  • Crystal structure
  • Molecular recognition
  • Neurotoxin
  • Nicotinic acetylcholine receptor

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera. / Huang, Sun; Li, Shu Xing; Bren, Nina; Cheng, Kevin; Gomoto, Ryan; Chen, Lin; Sine, Steven M.

In: Biochemical Journal, Vol. 454, No. 2, 01.09.2013, p. 303-310.

Research output: Contribution to journalArticle

Huang, Sun ; Li, Shu Xing ; Bren, Nina ; Cheng, Kevin ; Gomoto, Ryan ; Chen, Lin ; Sine, Steven M. / Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera. In: Biochemical Journal. 2013 ; Vol. 454, No. 2. pp. 303-310.
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