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基本情報
登録情報 | データベース: PDB / ID: 8bhk | ||||||
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タイトル | GABA-A receptor a5 homomer - a5V3 - Diazepam | ||||||
![]() | Gamma-aminobutyric acid receptor subunit alpha-5 | ||||||
![]() | MEMBRANE PROTEIN / pLGIC GABA Neurotransmission | ||||||
機能・相同性 | ![]() inhibitory extracellular ligand-gated monoatomic ion channel activity / benzodiazepine receptor activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / GABA receptor binding / inhibitory synapse assembly / innervation ...inhibitory extracellular ligand-gated monoatomic ion channel activity / benzodiazepine receptor activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / GABA receptor binding / inhibitory synapse assembly / innervation / synaptic transmission, GABAergic / postsynaptic specialization membrane / gamma-aminobutyric acid signaling pathway / cochlea development / neuronal cell body membrane / associative learning / chloride channel complex / GABA-ergic synapse / transmembrane transporter complex / behavioral fear response / regulation of postsynaptic membrane potential / chloride transmembrane transport / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / presynaptic membrane / signaling receptor activity / postsynapse / neuron projection / synapse / signal transduction / nucleoplasm / plasma membrane / cytosol 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.3 Å | ||||||
![]() | Miller, P.S. / Malinauskas, T.M. / Kasaragod, V.B. / Chirgadze, D.Y. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: The molecular basis of drug selectivity for α5 subunit-containing GABA receptors. 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 ...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 / ![]() ![]() 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. | ||||||
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-関連構造データ
関連構造データ | ![]() 16058MC ![]() 8bejC ![]() 8bgiC ![]() 8bhaC ![]() 8bhbC ![]() 8bhgC ![]() 8bhiC ![]() 8bhmC ![]() 8bhoC ![]() 8bhqC ![]() 8bhrC ![]() 8bhsC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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