EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	The molecular basis of drug selectivity for α5 subunit-containing GABA receptors.
ジャーナル・号・ページ	Nat Struct Mol Biol, Vol. 30, Issue 12, Page 1936-1946, Year 2023
掲載日	2023年10月30日
著者	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 要旨	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.
リンク	Nat Struct Mol Biol / PubMed:37903907 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	2.39 - 3.38 Å
構造データ	16005 8bej EMDB-16005, PDB-8bej: GABA-A receptor a5 homomer - a5V3 - APO 手法: EM (単粒子) / 解像度: 3.24 Å 16050 8bha EMDB-16050, PDB-8bha: GABA-A receptor a5 homomer - a5V3 - Basmisanil - HR 手法: EM (単粒子) / 解像度: 2.67 Å 16051 8bhb EMDB-16051, PDB-8bhb: GABA-A receptor a5 homomer - a5V3 - RO154513 手法: EM (単粒子) / 解像度: 2.54 Å 16055 8bhi EMDB-16055, PDB-8bhi: GABA-A receptor a5 homomer - a5V3 - RO5211223 手法: EM (単粒子) / 解像度: 2.67 Å 16058 8bhk EMDB-16058, PDB-8bhk: GABA-A receptor a5 homomer - a5V3 - Diazepam 手法: EM (単粒子) / 解像度: 3.3 Å 16060 8bhm EMDB-16060, PDB-8bhm: GABA-A receptor a5 homomer - a5V3 - DMCM 手法: EM (単粒子) / 解像度: 2.95 Å 16063 8bho EMDB-16063, PDB-8bho: GABA-A receptor a5 homomer - a5V3 - L655708 手法: EM (単粒子) / 解像度: 2.93 Å 16066 8bhq EMDB-16066, PDB-8bhq: GABA-A receptor a5 homomer - a5V3 - RO7172670 手法: EM (単粒子) / 解像度: 3.3 Å 16067 8bhr EMDB-16067, PDB-8bhr: GABA-A receptor a5 homomer - a5V3 - RO7015738 手法: EM (単粒子) / 解像度: 3.38 Å 16068 8bhs EMDB-16068, PDB-8bhs: GABA-A receptor a5 homomer - a5V3 - RO4938581 手法: EM (単粒子) / 解像度: 3.24 Å PDB-8bgi: GABA-A receptor a5 homomer - a5V1 - Flumazenil 手法: X-RAY DIFFRACTION / 解像度: 2.56 Å PDB-8bhg: GABA-A receptor a5 heteromer - a5V2 - Bretazenil 手法: X-RAY DIFFRACTION / 解像度: 2.39 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン ChemComp-SO4: SULFATE ION / 硫酸ジアニオン / 硫酸塩 ChemComp-FYP: ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / フルマゼニル / アンタゴニストYM / フルマゼニル ChemComp-P9N: Pregnanolone / プレグナノロン / 阻害剤YM / Pregnanolone ChemComp-HOH: WATER / 水 ChemComp-QI0: Basmisanil / バスミスアニル ChemComp-EIE: ethyl 8-[(azanylidene-$l^{4}-azanylidene)amino]-5-methyl-6-oxidanylidene-4~{H}-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / Ro-15-4513 / アンタゴニストYM / Ro15-4513 ChemComp-QMU: Bretazenil / ブレタゼニル ChemComp-DMU: DECYL-BETA-D-MALTOPYRANOSIDE / デシルβ-マルトシド / 可溶化剤YM ChemComp-NO3: NITRATE ION / 硝酸塩 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 / ジアゼパム / ジアゼパム ChemComp-R63: methyl 4-ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole-3-carboxylate / DMCM / 薬剤YM / 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 / L-655708 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
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / pLGIC GABA Neurotransmission