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TitleStructural and dynamic mechanisms of GABA receptor modulators with opposing activities.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 4582, Year 2022
Publish dateAug 6, 2022
AuthorsShaotong Zhu / Akshay Sridhar / Jinfeng Teng / Rebecca J Howard / Erik Lindahl / Ryan E Hibbs /
PubMed Abstractγ-Aminobutyric acid type A (GABA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and ...γ-Aminobutyric acid type A (GABA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA receptor allosteric modulators acting through a common site can have diverging activities.
External linksNat Commun / PubMed:35933426 / PubMed Central
MethodsEM (single particle)
Resolution2.9 Å
Structure data

27332

8dd2

EMDB-27332, PDB-8dd2:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus Zolpidem
Method: EM (single particle) / Resolution: 2.9 Å

27333

8dd3

EMDB-27333, PDB-8dd3:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus DMCM
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

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

ChemComp-R5R:
Zolpidem / medication*YM / Zolpidem

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

ChemComp-R63:
methyl 4-ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole-3-carboxylate / medication*YM / DMCM

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GABAA receptor / Zolpidem / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / Human GABAA receptor / DMCM

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