8zrp | pdb_00008zrp
Structure of nico
Structural highlights
FunctionACHA6_HUMAN Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate synaptic transmission in the nervous system and the neuromuscular junction. Each nAchR subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, cation permeability, and binding to allosteric modulators (Probable). CHRNA6 forms pentameric channels with CHRNB2, CHRNB3 and CHRNA4 that exhibit high sensitivity to ACh and nicotine and are predominantly expressed in only a few brain areas, including dopaminergic neurons, norepirephrine neurons and cells of the visual system (PubMed:16835356). nAChrs containing CHRNA6 subunits mediate endogenous cholinergic modulation of dopamine and gamma-aminobutyric acid (GABA) release in response to nicotine at nerve terminals.[UniProtKB:Q9R0W9][1] [2] Publication Abstract from PubMedThe alpha6beta4 nicotinic acetylcholine receptor (nAChR) is found in the sensory neurons of dorsal root ganglia. It is a promising therapeutic target for pain. However, the difficultly of heterologous functional expression of alpha6beta4 receptor has hindered the discovery of drugs that target it. Here, we functionally express the human alpha6beta4 receptor and determine the cryo-EM structures of alpha6beta4 receptor in complex with its agonists, nicotine and the preclinical drug tebanicline. These structures were captured in non-conducting desensitized states. We elucidate that the stoichiometry of alpha- and beta- subunits in the alpha6beta4 receptor is 2alpha6:3beta4. Furthermore, we identify the binding pockets for nicotine and tebanicline, demonstrating the essential residues contributing to ligand affinity and providing detailed molecular insights into why these agonists have different binding affinities despite both occupying the orthosteric site of the alpha6beta4 receptor. These structures offer significant molecular insight into the function and ligand recognition of alpha6beta4 receptor. Molecular insights into the alpha6beta4 nicotinic acetylcholine receptor function and ligand recognition.,Su J, Yu Z, Yin Z, Zhang Z, Zhao J, Meng Y, Li R, Gao Y, Zhang H, Yu R, Zhao Y Nat Commun. 2025 Apr 2;16(1):3153. doi: 10.1038/s41467-025-58333-0. PMID:40175361[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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