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Article Dans Une Revue EMBO Journal Année : 2007

AChBP‐targeted α‐conotoxin correlates distinct binding orientations with nAChR subtype selectivity

Regina Büttner
  • Fonction : Auteur
Alexander Fish
René van Elk
  • Fonction : Auteur
Yvonne Kendel
  • Fonction : Auteur
Gene Hopping
  • Fonction : Auteur
Paul F Alewood
  • Fonction : Auteur
Christina Schroeder
  • Fonction : Auteur
Annette Nicke
  • Fonction : Auteur
August B Smit
Titia K Sixma
  • Fonction : Auteur
Richard J Lewis
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-02306864 , version 1 (07-10-2019)

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Sébastien Dutertre, Chris Ulens, Regina Büttner, Alexander Fish, René van Elk, et al.. AChBP‐targeted α‐conotoxin correlates distinct binding orientations with nAChR subtype selectivity. EMBO Journal, 2007, 26 (16), pp.3858-3867. ⟨10.1038/sj.emboj.7601785⟩. ⟨hal-02306864⟩
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