| Structural highlights
Disease
GBRG2_HUMAN Childhood absence epilepsy;Dravet syndrome;Generalized epilepsy with febrile seizures-plus. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
GBRG2_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]
Publication Abstract from PubMed
alpha5 subunit-containing gamma-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 alpha5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the alpha5 subunit. These define the molecular basis of binding and alpha5 selectivity of the beta-carboline, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of alpha5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.
The molecular basis of drug selectivity for alpha5 subunit-containing GABA(A) receptors.,Kasaragod VB, Malinauskas T, Wahid AA, Lengyel J, Knoflach F, Hardwick SW, Jones CF, Chen WN, Lucas X, El Omari K, Chirgadze DY, Aricescu AR, Cecere G, Hernandez MC, Miller PS Nat Struct Mol Biol. 2023 Dec;30(12):1936-1946. doi: 10.1038/s41594-023-01133-1. , Epub 2023 Oct 30. PMID:37903907[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature. 1989 Apr 13;338(6216):582-5. PMID:2538761 doi:http://dx.doi.org/10.1038/338582a0
- ↑ Kasaragod VB, Malinauskas T, Wahid AA, Lengyel J, Knoflach F, Hardwick SW, Jones CF, Chen WN, Lucas X, El Omari K, Chirgadze DY, Aricescu AR, Cecere G, Hernandez MC, Miller PS. The molecular basis of drug selectivity for α5 subunit-containing GABA(A) receptors. Nat Struct Mol Biol. 2023 Oct 30. PMID:37903907 doi:10.1038/s41594-023-01133-1
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