AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity
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 a...
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Nature Publishing Group
2007
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952216/ |
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pubmed-19522162007-08-27 AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity Dutertre, Sébastien Ulens, Chris Büttner, Regina Fish, Alexander van Elk, René Kendel, Yvonne Hopping, Gene Alewood, Paul F Schroeder, Christina Nicke, Annette Smit, August B Sixma, Titia K Lewis, Richard J Article 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 α-conotoxin (α-TxIA) in the venom of Conus textile. α-TxIA bound with high affinity to AChBPs from different species and selectively targeted the α3β2 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. Nature Publishing Group 2007-08-22 2007-07-26 /pmc/articles/PMC1952216/ /pubmed/17660751 http://dx.doi.org/10.1038/sj.emboj.7601785 Text en Copyright © 2007, European Molecular Biology Organization http://creativecommons.org/licenses/by-nc-nd/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Dutertre, Sébastien Ulens, Chris Büttner, Regina Fish, Alexander van Elk, René Kendel, Yvonne Hopping, Gene Alewood, Paul F Schroeder, Christina Nicke, Annette Smit, August B Sixma, Titia K Lewis, Richard J |
| spellingShingle |
Dutertre, Sébastien Ulens, Chris Büttner, Regina Fish, Alexander van Elk, René Kendel, Yvonne Hopping, Gene Alewood, Paul F Schroeder, Christina Nicke, Annette Smit, August B Sixma, Titia K Lewis, Richard J AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity |
| author_facet |
Dutertre, Sébastien Ulens, Chris Büttner, Regina Fish, Alexander van Elk, René Kendel, Yvonne Hopping, Gene Alewood, Paul F Schroeder, Christina Nicke, Annette Smit, August B Sixma, Titia K Lewis, Richard J |
| author_sort |
Dutertre, Sébastien |
| title |
AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity |
| title_short |
AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity |
| title_full |
AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity |
| title_fullStr |
AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity |
| title_full_unstemmed |
AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity |
| title_sort |
achbp-targeted α-conotoxin correlates distinct binding orientations with nachr subtype selectivity |
| description |
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 α-conotoxin (α-TxIA) in the venom of Conus textile. α-TxIA bound with high affinity to AChBPs from different species and selectively targeted the α3β2 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. |
| publisher |
Nature Publishing Group |
| publishDate |
2007 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952216/ |
| _version_ |
1611399297346043904 |