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Gharpure A, Teng J, Zhuang Y, Noviello CM, Walsh RM, Cabuco R, Howard RJ, Zaveri NT, Lindahl E, Hibbs RE
Neuron 104 (3) 501-511.e6 [2019-11-06; online 2019-09-02]
Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3β4 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 α3β4 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 α3β4-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.
PubMed 31488329
DOI 10.1016/j.neuron.2019.07.030
Crossref 10.1016/j.neuron.2019.07.030
mid: NIHMS1536523
pmc: PMC6842111
pii: S0896-6273(19)30656-7