6pv8
Human alpha3beta4 nicotinic acetylcholine receptor in complex with AT-1001Human alpha3beta4 nicotinic acetylcholine receptor in complex with AT-1001
Structural highlights
FunctionACHA3_HUMAN After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Publication Abstract from PubMedNicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha3beta4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha3beta4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha3beta4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance. Agonist Selectivity and Ion Permeation in the alpha3beta4 Ganglionic Nicotinic Receptor.,Gharpure A, Teng J, Zhuang Y, Noviello CM, Walsh RM Jr, Cabuco R, Howard RJ, Zaveri NT, Lindahl E, Hibbs RE Neuron. 2019 Nov 6;104(3):501-511.e6. doi: 10.1016/j.neuron.2019.07.030. Epub, 2019 Sep 2. PMID:31488329[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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