8dd2
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus Zolpidem
Structural highlights
FunctionGBRB2_HUMAN Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.[1] [2] Publication Abstract from PubMedgamma-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 gamma-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 alpha/gamma subunit interface and two transmembrane sites at beta/alpha 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. Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities.,Zhu S, Sridhar A, Teng J, Howard RJ, Lindahl E, Hibbs RE Nat Commun. 2022 Aug 6;13(1):4582. doi: 10.1038/s41467-022-32212-4. PMID:35933426[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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