6D1S

Crystal structure of an apo chimeric human alpha1GABAA receptor

Summary for 6D1S

• Entry DOI: 10.2210/pdb6d1s/pdb
• Descriptor: chimeric alpha1GABAA receptor (1 entity in total)
• Functional Keywords: gabaa receptor, anesthetics, alphaxalone, neurosteroids, protein transport
• Biological source: Dickeya dadantii (strain 3937) (Erwinia chrysanthemi (strain 3937)); More
• Total number of polymer chains: 10
• Total formula weight: 372253.59

Authors

Chen, Q.,Arjunan, P.,Cohen, A.E.,Xu, Y.,Tang, P. (deposition date: 2018-04-12, release date: 2018-08-22, Last modification date: 2024-03-13)

Primary citation

Chen, Q.,Wells, M.M.,Arjunan, P.,Tillman, T.S.,Cohen, A.E.,Xu, Y.,Tang, P.
Structural basis of neurosteroid anesthetic action on GABAAreceptors.
Nat Commun, 9:3972-3972, 2018

PubMed Abstract: Type A γ-aminobutyric acid receptors (GABARs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABAR transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABAR structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABAR (ELIC-α1GABAR). The chimera retains the functional and pharmacological properties of GABARs, 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 GABAR modulators with therapeutic potential.

PubMed: 30266951
DOI: 10.1038/s41467-018-06361-4

Experimental method

X-RAY DIFFRACTION (3.2 Å)