TY  - JOUR
A1  - Dutertre, Sébastien
A1  - Ulens, Chris
A1  - Büttner, Regina
A1  - Fish, Alexander
A1  - Elk, René van
A1  - Kendel, Yvonne
A1  - Hopping, Gene
A1  - Alewood, Paul F.
A1  - Schroeder, Christina
A1  - Nicke, Annette
A1  - Smit, August B.
A1  - Sixma, Titia K.
A1  - Lewis, Richard J.
T1  - AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity
T2  - The EMBO journal
N2  - 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 alpha3beta2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° 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.
KW  - acetylcholine binding protein
KW  - conotoxin
KW  - cys-loop receptor
KW  - ion channel
KW  - nicotinic acetylcholine receptors
Y1  - 2007
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/7148
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30-64404
SN  - 1460-2075
SN  - 0261-4189
N1  - This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
VL  - 26
IS  - 16
SP  - 3858
EP  - 3867
PB  - Nature Publ. Group
CY  - London [u. a.]
ER  -