登録情報 データベース : EMDB / ID : EMD-33628 ダウンロードとリンクタイトル CryoEM structure of PS2-containing gamma-secretase treated with MRK-560 マップデータCryoEM structure of PS2-containing gamma-secretase treated with MRK-560 詳細 試料複合体 : PS2-containing gamma-secretase complex treated with MRK-560タンパク質・ペプチド : Nicastrinタンパク質・ペプチド : Presenilin-2 PSEN2タンパク質・ペプチド : Gamma-secretase subunit APH-1A Γ-セクレターゼタンパク質・ペプチド : Gamma-secretase subunit PEN-2 Γ-セクレターゼリガンド : 2-acetamido-2-deoxy-beta-D-glucopyranoseリガンド : 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINEリガンド : CHOLESTEROL コレステロール 詳細機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
regulation of calcium import into the mitochondrion / : / amyloid precursor protein biosynthetic process / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / positive regulation of endopeptidase activity / Notch receptor processing ... regulation of calcium import into the mitochondrion / : / amyloid precursor protein biosynthetic process / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / positive regulation of endopeptidase activity / Notch receptor processing / central nervous system myelination / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus / growth factor receptor binding / Regulated proteolysis of p75NTR / metanephros development / glutamate receptor signaling pathway / amyloid precursor protein metabolic process / regulation of long-term synaptic potentiation / nuclear inner membrane / 繊毛 / myeloid cell homeostasis / azurophil granule membrane / dopamine receptor signaling pathway / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; アスパラギン酸プロテアーゼ / Golgi cisterna membrane / adult behavior / mitochondrion-endoplasmic reticulum membrane tethering / positive regulation of catalytic activity / amyloid precursor protein catabolic process / plasma membrane => GO:0005886 / amyloid-beta formation / membrane protein ectodomain proteolysis / endopeptidase activator activity / EPH-ephrin mediated repulsion of cells / amyloid-beta metabolic process / T cell proliferation / Nuclear signaling by ERBB4 / Notchシグナリング / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / Degradation of the extracellular matrix / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / dendritic shaft / epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / neuromuscular junction / protein processing / 筋鞘 / 動原体 / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Z disc / calcium ion transport / メラノソーム / シナプス小胞 / protein-macromolecule adaptor activity / presynaptic membrane / 細胞皮質 / ATPase binding / 成長円錐 / neuron apoptotic process / endopeptidase activity / ミトコンドリア内膜 / エンドソーム / learning or memory / endosome membrane / response to hypoxia / intracellular signal transduction / 脂質ラフト / apical plasma membrane / Amyloid fiber formation / lysosomal membrane / ゴルジ体 / focal adhesion / 中心体 / neuronal cell body / Neutrophil degranulation / endoplasmic reticulum membrane / negative regulation of apoptotic process / perinuclear region of cytoplasm / ゴルジ体 / enzyme binding / 細胞膜 / 小胞体 / protein-containing complex / タンパク質分解 / extracellular exosome / 生体膜 / 細胞核 / 細胞膜 類似検索 - 分子機能 Peptidase A22A, presenilin 2 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / プレセニリン / Nicastrin / Nicastrin, small lobe ... Peptidase A22A, presenilin 2 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / プレセニリン / Nicastrin / Nicastrin, small lobe / Nicastrin / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family 類似検索 - ドメイン・相同性 Presenilin-2 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2 類似検索 - 構成要素生物種 Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.0 Å 詳細 データ登録者Guo X / Wang Y / Zhou J / Jin C / Wang J / Jia B / Jing D / Yan C / Lei J / Zhou R / Shi Y 資金援助 中国, 1件 詳細 詳細を隠すOrganization Grant number 国 National Natural Science Foundation of China (NSFC) 81920108015 中国
引用ジャーナル : Nat Commun / 年 : 2022タイトル : Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.著者 : Xuefei Guo / Yumeng Wang / Jiayao Zhou / Chen Jin / Jiaoni Wang / Bojun Jia / Dan Jing / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi / 要旨 : Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, ... Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of γ-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing γ-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 Å. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting γ-secretase. 履歴 登録 2022年6月17日 - ヘッダ(付随情報) 公開 2022年11月2日 - マップ公開 2022年11月2日 - 更新 2022年11月2日 - 現状 2022年11月2日 処理サイト : PDBj / 状態 : 公開
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