National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)
DA047325
米国
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)
DA042072
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS095899
米国
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)
DA037492
米国
American Heart Association
18POST34030412
米国
Welch Foundation
I-1812
米国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Structural and dynamic mechanisms of GABA receptor modulators with opposing activities. 著者: Shaotong Zhu / Akshay Sridhar / Jinfeng Teng / Rebecca J Howard / Erik Lindahl / Ryan E Hibbs / 要旨: 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 ...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.