Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities

Zhu, Shaotong; Sridhar, Akshay; Teng, Jinfeng; Howard, Rebecca J.; Lindahl, Erik; Hibbs, Ryan E.

doi:10.1038/s41467-022-32212-4

Title: Structural and dynamic mechanisms of GABA_A receptor modulators with opposing activities

Journal Article · 06 August 2022 · Nature Communications

DOI: https://doi.org/10.1038/s41467-022-32212-4 · OSTI ID:1903929

Zhu, Shaotong ^[1]; Sridhar, Akshay ^[2]; Teng, Jinfeng ^[3];

^[4];

^[5];

^[3]

University of Texas Southwestern Medical Center, Dallas, TX (United States); OSTI
KTH Royal Institute of Technology, Solna (Sweden)
University of Texas Southwestern Medical Center, Dallas, TX (United States)
Stockholm University (Sweden)
KTH Royal Institute of Technology, Solna (Sweden); Stockholm University (Sweden)

γ-Aminobutyric acid type A (GABA_A) 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_A) 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_A 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_A receptor allosteric modulators acting through a common site can have diverging activities.

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Research Organization:: University of Texas Southwestern Medical Center, Dallas, TX (United States)

Sponsoring Organization:: Marie Sklodowska-Curie; National Institutes of Health (NIH); Swedish Research Council; Swedish e-Science Research Center; USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER); Welch Foundation

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1903929

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Structural and dynamic mechanisms of GABA_A receptor modulators with opposing activities