8SID

Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus dehydroepiandrosterone sulfate

Summary for 8SID

• Entry DOI: 10.2210/pdb8sid/pdb
• EMDB information: 40503 40506
• Descriptor: Gamma-aminobutyric acid receptor subunit beta-2, GAMMA-AMINO-BUTANOIC ACID, 17-oxoandrost-5-en-3beta-yl hydrogen sulfate, ... (14 entities in total)
• Functional Keywords: ion channel, neurosteroids, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 370900.71

Authors

Legesse, D.H.,Hibbs, R.E. (deposition date: 2023-04-14, release date: 2023-08-30, Last modification date: 2024-10-23)

Primary citation

Legesse, D.H.,Fan, C.,Teng, J.,Zhuang, Y.,Howard, R.J.,Noviello, C.M.,Lindahl, E.,Hibbs, R.E.
Structural insights into opposing actions of neurosteroids on GABA A receptors.
Nat Commun, 14:5091-5091, 2023

PubMed Abstract: γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.

PubMed: 37607940
DOI: 10.1038/s41467-023-40800-1

Experimental method

ELECTRON MICROSCOPY (2.71 Å)