Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)‐anatoxin‐a and (−)‐hosieine‐A. Issue 9 (9th August 2022)

• Record Type: Journal Article
• Authors: Parker, Holly P.; Dawson, Alice; Jones, Mathew J.; Yan, Rui; Ouyang, Jie; Hong, Ran; Hunter, William N.
• Is Part Of: Acta crystallographica. Volume 78:Issue 9(2022)
• Page Start: 313
• Page End: 323
• Publication Date: 2022-08-09
• Subjects: acetylcholine‐binding proteins -- (+)‐anatoxin‐a -- (−)‐hosieine‐A -- crystal structure -- ligand‐gated ion channels -- neurotoxins -- nicotine -- nicotinic acetylcholine receptors -- varenicline; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X22007762
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : The binding of two potent alkaloid neurotoxins to acetylcholine‐binding protein was investigated using calorimetry and fluorescence titration. The crystal structures of two complexes and sequence and structure comparisons inform discussion on the biological implications for interactions with human nicotinic acetylcholine receptor subtypes, which are important therapeutic targets. 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 ( Ac AChBP) were determined and reveal details of molecular recognition in the orthosteric binding site. Comparisons treating Ac AChBP 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 Ac AChBP 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.