| Structural highlights
8dd3 is a 9 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.9Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GBRB2_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 PubMed
gamma-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
- ↑ Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, Yu Z, Pun FW, Ren L, Lo WS, Tsang SY, Xue H. Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. PLoS One. 2009 Sep 18;4(9):e6977. doi: 10.1371/journal.pone.0006977. PMID:19763268 doi:http://dx.doi.org/10.1371/journal.pone.0006977
- ↑ Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI, et al.. Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors. Mol Pharmacol. 1993 Dec;44(6):1211-8. PMID:8264558
- ↑ Zhu S, Sridhar A, Teng J, Howard RJ, Lindahl E, Hibbs RE. Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities. Nat Commun. 2022 Aug 6;13(1):4582. PMID:35933426 doi:10.1038/s41467-022-32212-4
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