The molecular basis of drug selectivity for α5 subunit-containing GABA_A receptors.

ABSTRACT: α5 subunit-containing γ-aminobutyric acid type A (GABA_A) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appear

SUBMITTER: Kasaragod VB 

PROVIDER: S-EPMC10716045 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature