AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity

Dutertre, S., Ulens, C, Buttner, R, Fish, A, van Elk, R, Kendel, Y, Hopping, G., Alewood, P. F., Schroeder, C., Nicke, A, Smit, AB, Sixma, TK and Lewis, R. J. (2007) AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity. Embo Journal, 26 16: 3858-3867.


Author Dutertre, S.
Ulens, C
Buttner, R
Fish, A
van Elk, R
Kendel, Y
Hopping, G.
Alewood, P. F.
Schroeder, C.
Nicke, A
Smit, AB
Sixma, TK
Lewis, R. J.
Title AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity
Journal name Embo Journal   Check publisher's open access policy
ISSN 0261-4189
Publication date 2007
Sub-type Article (original research)
DOI 10.1038/sj.emboj.7601785
Volume 26
Issue 16
Start page 3858
End page 3867
Total pages 10
Editor Rorth, P.
Place of publication London
Publisher European Molecular Biology Organisation
Collection year 2008
Language eng
Subject C1
250302 Biological and Medical Chemistry
780105 Biological sciences
780103 Chemical sciences
Abstract Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand- binding domain, to discover a novel alpha-conotoxin (alpha-TxIA) in the venom of Conus textile. alpha-TxIA bound with high affinity to AChBPs from different species and selectively targeted the alpha(3)beta(2) nAChR subtype. A co-crystal structure of Ac- AChBP with the enhanced potency analog TxIA(A10L), revealed a 201 backbone tilt compared to other AChBP - conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases.
Keyword Biochemistry & Molecular Biology
Cell Biology
acetylcholine binding protein
conotoxin
cys-loop receptor
ion channel
nicotinic acetylcholine receptors
Nicotinic-acetylcholine-receptor
Crystal-structure
Homolog Achbp
Protein
Determinants
Refinement
Complexes
Peptides
Reveals
Ligand
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Mon, 18 Feb 2008, 14:54:47 EST