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PDBsum entry 5ojm
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Membrane protein
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PDB id
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5ojm
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References listed in PDB file
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Key reference
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Title
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Structural basis for gabaareceptor potentiation by neurosteroids.
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Authors
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P.S.Miller,
S.Scott,
S.Masiulis,
L.De colibus,
E.Pardon,
J.Steyaert,
A.R.Aricescu.
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Ref.
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Nat Struct Mol Biol, 2017,
24,
986-992.
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PubMed id
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Abstract
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Type A γ-aminobutyric acid receptors (GABAARs) are the principal
mediators of inhibitory neurotransmission in the human brain. Endogenous
neurosteroids interact with GABAARs to regulate acute and chronic
anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic
agents. Their mode of binding and mechanism of receptor potentiation, however,
remain unknown. Here we report crystal structures of a chimeric
GABAAR construct in apo and pregnanolone-bound states. The
neurosteroid-binding site is mechanically coupled to the helices lining the ion
channel pore and modulates the desensitization-gate conformation. We demonstrate
that the equivalent site is responsible for physiological, heteromeric
GABAAR potentiation and explain the contrasting modulatory properties
of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral
lipid ligands can regulate the desensitization gate of GABAARs, a
process of broad relevance to pentameric ligand-gated ion channels.
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