Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (−)-hosieine-A

Holly P. Parker, Alice Dawson, M. J. Jones, Rui Yan, Jie Ouyang, Ran Hong, William N. Hunter (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
31 Downloads (Pure)

Abstract

The affinity and thermodynamic parameters for the interactions of two naturally occurring neurotoxins, (+)-anatoxin-a and (-)-hosieine-A, with acetylcholine-binding protein were investigated using a fluorescence-quenching assay and isothermal titration calorimetry. The crystal structures of their complexes with acetylcholine-binding protein from Aplysia californica (AcAChBP) were determined and reveal details of molecular recognition in the orthosteric binding site. Comparisons treating AcAChBP as a surrogate for human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the molecular features involved in ligand recognition and affinity for the protein targets are conserved. The ligands exploit interactions with similar residues as the archetypal nAChR agonist nicotine, but with greater affinity. (-)-Hosieine-A in particular has a high affinity for AcAChBP driven by a favorable entropic contribution to binding. The ligand affinities help to rationalize the potent biological activity of these alkaloids. The structural data, together with comparisons with related molecules, suggest that there may be opportunities to extend the hosieine-A scaffold to incorporate new interactions with the complementary side of the orthosteric binding site. Such a strategy may guide the design of new entities to target human α4β2 nAChR that may have therapeutic benefit.

Original languageEnglish
Pages (from-to)313-323
Number of pages11
JournalActa Crystallographica Section F: Structural Biology Communications
VolumeF78
Issue number9
Early online date9 Aug 2022
DOIs
Publication statusPublished - 1 Sept 2022

Keywords

  • acetylcholine-binding proteins
  • (+)-anatoxin-a
  • (−)-hosieine-A
  • crystal structure
  • ligand-gated ion channels
  • neurotoxins
  • nicotine
  • nicotinic acetylcholine receptors
  • varenicline

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