Comparative Study on the Use of Docking and Bayesian Categorization To Predict Ligand Binding to Nicotinic Acetylcholine Receptors (nAChRs) Subtypes

2013 ◽  
Vol 53 (12) ◽  
pp. 3212-3222 ◽  
Author(s):  
David C. Kombo ◽  
Merouane Bencherif
Keyword(s):  
Ligand Binding ◽  
Comparative Study ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
Bayesian Categorization

scholarly journals Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

2020 ◽  
Vol 14 ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Rational Drug Design ◽  
Comprehensive Overview ◽  
Nicotinic Acetylcholine ◽  
Structure Based Drug Design ◽  
Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

scholarly journals Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products

2020 ◽  
Vol 117 (39) ◽  
pp. 24534-24544
Author(s):  
Shenyan Gu ◽  
Daniel Knowland ◽  
Jose A. Matta ◽  
Min L. O’Carroll ◽  
Weston B. Davini ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Hair Cells ◽  
Acetylcholine Receptors ◽  
Functional Expression ◽  
Acoustic Trauma ◽  
Cholinergic Innervation ◽  
Nicotinic Acetylcholine ◽  
Auditory Hair Cells ◽  
Mammalian Cell Lines

Auditory hair cells receive olivocochlear efferent innervation, which refines tonotopic mapping, improves sound discrimination, and mitigates acoustic trauma. The olivocochlear synapse involves α9α10 nicotinic acetylcholine receptors (nAChRs), which assemble in hair cells only coincident with cholinergic innervation and do not express in recombinant mammalian cell lines. Here, genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and retain α9α10-mediated transmission beyond the second postnatal week associated with abnormally persistent cholinergic innervation. Collectively, this study provides a mechanism to link cholinergic input with α9α10 assembly, identifies unexpected functions for human deafness genes TMIE/TMEM132e, and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders.

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