Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	The molecular basis of drug selectivity for α5 subunit-containing GABA receptors.
Journal, issue, pages	Nat Struct Mol Biol, Vol. 30, Issue 12, Page 1936-1946, Year 2023
Publish date	Oct 30, 2023
Authors	Vikram Babu Kasaragod / Tomas Malinauskas / Ayla A Wahid / Judith Lengyel / Frederic Knoflach / Steven W Hardwick / Charlotte F Jones / Wan-Na Chen / Xavier Lucas / Kamel El Omari / Dimitri Y Chirgadze / A Radu Aricescu / Giuseppe Cecere / Maria-Clemencia Hernandez / Paul S Miller /
PubMed Abstract	α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to ...α5 subunit-containing γ-aminobutyric acid type A (GABA) 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 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 α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.
External links	Nat Struct Mol Biol / PubMed:37903907 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	2.39 - 3.38 Å
Structure data	16005 8bej EMDB-16005, PDB-8bej: GABA-A receptor a5 homomer - a5V3 - APO Method: EM (single particle) / Resolution: 3.24 Å 16050 8bha EMDB-16050, PDB-8bha: GABA-A receptor a5 homomer - a5V3 - Basmisanil - HR Method: EM (single particle) / Resolution: 2.67 Å 16051 8bhb EMDB-16051, PDB-8bhb: GABA-A receptor a5 homomer - a5V3 - RO154513 Method: EM (single particle) / Resolution: 2.54 Å 16055 8bhi EMDB-16055, PDB-8bhi: GABA-A receptor a5 homomer - a5V3 - RO5211223 Method: EM (single particle) / Resolution: 2.67 Å 16058 8bhk EMDB-16058, PDB-8bhk: GABA-A receptor a5 homomer - a5V3 - Diazepam Method: EM (single particle) / Resolution: 3.3 Å 16060 8bhm EMDB-16060, PDB-8bhm: GABA-A receptor a5 homomer - a5V3 - DMCM Method: EM (single particle) / Resolution: 2.95 Å 16063 8bho EMDB-16063, PDB-8bho: GABA-A receptor a5 homomer - a5V3 - L655708 Method: EM (single particle) / Resolution: 2.93 Å 16066 8bhq EMDB-16066, PDB-8bhq: GABA-A receptor a5 homomer - a5V3 - RO7172670 Method: EM (single particle) / Resolution: 3.3 Å 16067 8bhr EMDB-16067, PDB-8bhr: GABA-A receptor a5 homomer - a5V3 - RO7015738 Method: EM (single particle) / Resolution: 3.38 Å 16068 8bhs EMDB-16068, PDB-8bhs: GABA-A receptor a5 homomer - a5V3 - RO4938581 Method: EM (single particle) / Resolution: 3.24 Å PDB-8bgi: GABA-A receptor a5 homomer - a5V1 - Flumazenil Method: X-RAY DIFFRACTION / Resolution: 2.56 Å PDB-8bhg: GABA-A receptor a5 heteromer - a5V2 - Bretazenil Method: X-RAY DIFFRACTION / Resolution: 2.39 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine ChemComp-SO4: SULFATE ION / Sulfate ChemComp-FYP: ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / antagonistYM / Flumazenil ChemComp-P9N: Pregnanolone / inhibitorYM / Pregnanolone ChemComp-HOH: WATER / Water ChemComp-QI0: Basmisanil ChemComp-EIE: ethyl 8-[(azanylidene-$l^{4}-azanylidene)amino]-5-methyl-6-oxidanylidene-4~{H}-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / antagonistYM / Ro15-4513 ChemComp-QMU: Bretazenil ChemComp-DMU: DECYL-BETA-D-MALTOPYRANOSIDE / detergentYM ChemComp-NO3: NITRATE ION / Nitrate ChemComp-QKF: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone ChemComp-DZP: 7-CHLORO-1-METHYL-5-PHENYL-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE / Diazepam ChemComp-R63: methyl 4-ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole-3-carboxylate / medicationYM / DMCM ChemComp-QMJ: ethyl (7~{S})-15-methoxy-12-oxidanylidene-2,4,11-triazatetracyclo[11.4.0.0^{2,6}.0^{7,11}]heptadeca-1(17),3,5,13,15-pentaene-5-carboxylate ChemComp-QR3: 2-[[5-methyl-3-(6-methylpyridazin-3-yl)-1,2-oxazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3-one ChemComp-QM7: 6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]-~{N}-[(2~{S})-1-oxidanylpentan-2-yl]pyridine-3-carboxamide ChemComp-QK9*: 5-[bis(fluoranyl)methyl]-15-bromanyl-2,4,8,9,11-pentazatetracyclo[11.4.0.0^{2,6}.0^{8,12}]heptadeca-1(13),3,5,9,11,14,16-heptaene
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN / pLGIC GABA Neurotransmission