| Structural highlights
8sgo 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 2.65Å |
| 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 mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA(A) receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA(A) receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA(A) receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
Structural insights into opposing actions of neurosteroids on GABA(A) receptors.,Legesse DH, Fan C, Teng J, Zhuang Y, Howard RJ, Noviello CM, Lindahl E, Hibbs RE Nat Commun. 2023 Aug 22;14(1):5091. doi: 10.1038/s41467-023-40800-1. PMID:37607940[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
- ↑ Legesse DH, Fan C, Teng J, Zhuang Y, Howard RJ, Noviello CM, Lindahl E, Hibbs RE. Structural insights into opposing actions of neurosteroids on GABA(A) receptors. Nat Commun. 2023 Aug 22;14(1):5091. PMID:37607940 doi:10.1038/s41467-023-40800-1
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