Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera.
Biochem J
; 454(2): 303-310, 2013 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-23800261
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 Asp³° 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.
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Base de dados:
MEDLINE
Assunto principal:
Bungarotoxinas
/
Proteínas de Transporte
/
Modelos Moleculares
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Receptores Nicotínicos
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Proteínas de Répteis
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Neurotoxinas
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos