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- W2892600712 abstract "Abstract Type A γ-aminobutyric acid receptors (GABA A Rs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABA A R transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABA A R structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABA A R (ELIC-α1GABA A R). The chimera retains the functional and pharmacological properties of GABA A Rs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1–TM2 linker. The study provides a framework to discover new GABA A R modulators with therapeutic potential." @default.
- W2892600712 created "2018-10-05" @default.
- W2892600712 creator A5017520377 @default.
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- W2892600712 date "2018-09-28" @default.
- W2892600712 modified "2023-10-12" @default.
- W2892600712 title "Structural basis of neurosteroid anesthetic action on GABAA receptors" @default.
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- W2892600712 doi "https://doi.org/10.1038/s41467-018-06361-4" @default.
- W2892600712 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6162318" @default.
- W2892600712 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30266951" @default.
- W2892600712 hasPublicationYear "2018" @default.
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