A Structural Rationale for <i>N</i>‐Methylbicuculline Acting as a Promiscuous Competitive Antagonist of Inhibitory Pentameric Ligand‐Gated Ion Channels

Jones, Mathew J.; Dawson, Alice; Hales, Tim G.; Hunter, William N.

doi:10.1002/cbic.201900680

Cited by 3 publications

(2 citation statements)

References 40 publications

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“…Alternatively, cooperativity or allosteric transitions can complicate the analyses. We have not uncovered any proof for such behavior in AcAChBP in this or previous studies (Dawson et al, 2019;Jones et al, 2020) and are unable to shed further light on these observations relating to carbamylcholine or 2.…”

Section: Thermodynamic Parameterscontrasting

confidence: 68%

The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica

et al. 2020

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Cytisine, a natural product with high affinity for clinically relevant nicotinic acetylcholine receptors (nAChRs), is used as a smoking‐cessation agent. The compound displays an excellent clinical profile and hence there is an interest in derivatives that may be further improved or find use in the treatment of other conditions. Here, the binding of a cytisine derivative modified by the addition of a 3‐(hydroxypropyl) moiety (ligand 4) to Aplysia californica acetylcholine‐binding protein (AcAChBP), a surrogate for nAChR orthosteric binding sites, was investigated. Isothermal titration calorimetry revealed that the favorable binding of cytisine and its derivative to AcAChBP is driven by the enthalpic contribution, which dominates an unfavorable entropic component. Although ligand 4 had a less unfavorable entropic contribution compared with cytisine, the affinity for AcAChBP was significantly diminished owing to the magnitude of the reduction in the enthalpic component. The high‐resolution crystal structure of the AcAChBP–4 complex indicated close similarities in the protein–ligand interactions involving the parts of 4 common to cytisine. The point of difference, the 3‐(hydroxypropyl) substituent, appears to influence the conformation of the Met133 side chain and helps to form an ordered solvent structure at the edge of the orthosteric binding site.

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Section: Thermodynamic Parameterscontrasting

confidence: 68%

The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica

et al. 2020

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“…It has previously been noted based on ITC data (Celie et al, 2004;Jones et al, 2020) that some ligands, for example carbamylcholine, bind AcAChBP with N values of around 0.5. Similar observations are made in the present work, with N values of 0.4-0.7 being noted (Table 4).…”

Section: Binding Studiesmentioning

confidence: 99%

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

Parker¹,

Dawson²,

Jones³

et al. 2022

Acta Crystallogr F Struct Biol Commun

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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.

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Gamma-aminobutyric acid (GABA) suppresses hemocyte phagocytosis by binding to GABA receptors and modulating corresponding downstream pathways in blood clam, Tegillarca granosa

Tian

et al. 2023

Fish & Shellfish Immunology

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A Structural Rationale for N‐Methylbicuculline Acting as a Promiscuous Competitive Antagonist of Inhibitory Pentameric Ligand‐Gated Ion Channels

Cited by 3 publications

References 40 publications

The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica

The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica

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

Gamma-aminobutyric acid (GABA) suppresses hemocyte phagocytosis by binding to GABA receptors and modulating corresponding downstream pathways in blood clam, Tegillarca granosa

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