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TitleAgonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor.
Journal, issue, pagesNeuron, Vol. 104, Issue 3, Page 501-511.e6, Year 2019
Publish dateNov 6, 2019
AuthorsAnant Gharpure / Jinfeng Teng / Yuxuan Zhuang / Colleen M Noviello / Richard M Walsh / Rico Cabuco / Rebecca J Howard / Nurulain T Zaveri / Erik Lindahl / Ryan E Hibbs /
PubMed AbstractNicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3β4 nicotinic receptor subtype forms the principal relay between the central and ...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.
External linksNeuron / PubMed:31488329 / PubMed Central
MethodsEM (single particle)
Resolution3.34 - 4.7 Å
Structure data

EMDB-20487, PDB-6pv7:
Human alpha3beta4 nicotinic acetylcholine receptor in complex with nicotine
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-20488, PDB-6pv8:
Human alpha3beta4 nicotinic acetylcholine receptor in complex with AT-1001
Method: EM (single particle) / Resolution: 3.87 Å

EMDB-20489:
Human alpha3beta4 nicotinic acetylcholine receptor in complex with nicotine in saposin nanodiscs without CHS
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-20490:
Human alpha3beta4 nicotinic acetylcholine receptor in complex with AT-1001 in saposin nanodiscs
Method: EM (single particle) / Resolution: 4.55 Å

Chemicals

ChemComp-NCT:
(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / alkaloid*YM

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-NA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-DD9:
nonane

ChemComp-HOH:
WATER

ChemComp-P1M:
(3-endo)-N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine

Source
  • homo sapiens (human)
  • house mouse (house mouse)
  • escherichia coli o11 (bacteria)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Ligand-gated ion channel / Nicotinic acetylcholine receptor / Cys-loop receptor

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