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基本情報
登録情報 | データベース: PDB / ID: 8bhg | ||||||
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タイトル | GABA-A receptor a5 heteromer - a5V2 - Bretazenil | ||||||
![]() | (Gamma-aminobutyric acid receptor subunit ...) x 2 | ||||||
![]() | MEMBRANE PROTEIN / pLGIC GABA Neurotransmission | ||||||
機能・相同性 | ![]() benzodiazepine receptor activity / GABA receptor binding / cellular response to histamine / GABA receptor activation / inner ear receptor cell development / inhibitory synapse assembly / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / innervation ...benzodiazepine receptor activity / GABA receptor binding / cellular response to histamine / GABA receptor activation / inner ear receptor cell development / inhibitory synapse assembly / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / innervation / postsynaptic specialization membrane / neuronal cell body membrane / gamma-aminobutyric acid signaling pathway / synaptic transmission, GABAergic / chloride channel activity / adult behavior / associative learning / cochlea development / Signaling by ERBB4 / behavioral fear response / chloride channel complex / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / cytoplasmic vesicle membrane / chloride transmembrane transport / post-embryonic development / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / GABA-ergic synapse / signaling receptor activity / presynaptic membrane / dendritic spine / postsynaptic membrane / postsynapse / axon / signal transduction / nucleoplasm / plasma membrane / cytosol 類似検索 - 分子機能 | ||||||
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![]() | Miller, P.S. / Malinauskas, T.M. / Omari, K.E. / Aricescu, A.R. | ||||||
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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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文書・要旨 | ![]() | 3.1 MB | 表示 | ![]() |
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-関連構造データ
関連構造データ | ![]() 8bejC ![]() 8bgiC ![]() 8bhaC ![]() 8bhbC ![]() 8bhiC ![]() 8bhkC ![]() 8bhmC ![]() 8bhoC ![]() 8bhqC ![]() 8bhrC ![]() 8bhsC ![]() 4cofS S: 精密化の開始モデル C: 同じ文献を引用 ( |
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