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Structure paper

TitleStructural insights into opposing actions of neurosteroids on GABA receptors.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5091, Year 2023
Publish dateAug 22, 2023
AuthorsDagimhiwat H Legesse / Chen Fan / Jinfeng Teng / Yuxuan Zhuang / Rebecca J Howard / Colleen M Noviello / Erik Lindahl / Ryan E Hibbs /
PubMed Abstractγ-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 ...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.
External linksNat Commun / PubMed:37607940 / PubMed Central
MethodsEM (single particle)
Resolution2.65 - 2.98 Å
Structure data

40462

8sgo

EMDB-40462, PDB-8sgo:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus pregnenolone sulfate
Method: EM (single particle) / Resolution: 2.65 Å

40503

8si9

EMDB-40503, PDB-8si9:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus allopregnanolone
Method: EM (single particle) / Resolution: 2.98 Å

40506

8sid

EMDB-40506, PDB-8sid:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus dehydroepiandrosterone sulfate
Method: EM (single particle) / Resolution: 2.71 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM / Γ-Aminobutyric acid

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

ChemComp-Q3G:
O-[(R)-[(2S)-2-(hexadecanoyloxy)-3-(octadecanoyloxy)propoxy](hydroxy)phosphoryl]-D-serine / phospholipid*YM

ChemComp-A8W:
Pregnenolone sulfate / antidepressant*YM / Pregnenolone sulfate

ChemComp-Y4B:
allopregnanolone

ChemComp-ZWY:
17-oxoandrost-5-en-3beta-yl hydrogen sulfate

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM / Ion channel / neurosteroids / TRANSPORT PROTEIN-IMMUNE SYSTEM complex / TRANSPORT PROTEIN

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