登録情報 データベース : PDB / ID : 7d8x 構造の表示 ダウンロードとリンクタイトル CryoEM structure of human gamma-secretase in complex with E2012 and L685458 要素(Gamma-secretase subunit ...) x 2 Nicastrin Presenilin-1 詳細キーワード HYDROLASE / inhibitor / modulator / membrane protein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
Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process ... Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process / positive regulation of endopeptidase activity / Noncanonical activation of NOTCH3 / sequestering of calcium ion / Notch receptor processing / choline transport / central nervous system myelination / synaptic vesicle targeting / membrane protein intracellular domain proteolysis / negative regulation of axonogenesis / regulation of resting membrane potential / T cell activation involved in immune response / NOTCH4 Activation and Transmission of Signal to the Nucleus / skin morphogenesis / growth factor receptor binding / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / cerebral cortex cell migration / regulation of phosphorylation / metanephros development / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / glutamate receptor signaling pathway / locomotion / amyloid precursor protein metabolic process / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / aggresome / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / skeletal system morphogenesis / cell fate specification / ciliary rootlet / myeloid cell homeostasis / regulation of postsynapse organization / azurophil granule membrane / G protein-coupled 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 / positive regulation of amyloid fibril formation / Golgi cisterna membrane / adult behavior / mitochondrial transport / positive regulation of dendritic spine development / positive regulation of receptor recycling / blood vessel development / regulation of neuron projection development / heart looping / protein glycosylation / amyloid precursor protein catabolic process / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / endopeptidase activator activity / autophagosome assembly / EPH-ephrin mediated repulsion of cells / smooth endoplasmic reticulum / neuron development / hematopoietic progenitor cell differentiation / negative regulation of ubiquitin-dependent protein catabolic process / somitogenesis / calcium ion homeostasis / T cell proliferation / Nuclear signaling by ERBB4 / rough endoplasmic reticulum / epithelial cell proliferation / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / Degradation of the extracellular matrix / positive regulation of glycolytic process / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / post-embryonic development / thymus development / negative regulation of protein phosphorylation / dendritic shaft / PDZ domain binding / apoptotic signaling pathway / cell-cell adhesion / synapse organization 類似検索 - 分子機能 Peptidase A22A, presenilin 1 / 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 / Presenilin / Nicastrin / Nicastrin, small lobe ... Peptidase A22A, presenilin 1 / 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 / Presenilin / 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 CHOLESTEROL / Chem-FTO / Chem-GZR / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PHOSPHATIDYLETHANOLAMINE / Presenilin-1 / 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 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 : 2.6 Å 詳細データ登録者 Yang, G. / Zhou, R. / Guo, X. / Lei, J. / Yan, C. / Shi, Y. 資金援助 中国, 1件 詳細 詳細を隠す組織 認可番号 国 National Natural Science Foundation of China (NSFC) 81920108015 中国
引用ジャーナル : Cell / 年 : 2021タイトル : Structural basis of γ-secretase inhibition and modulation by small molecule drugs.著者 : Guanghui Yang / Rui Zhou / Xuefei Guo / Chuangye Yan / Jianlin Lei / Yigong Shi / 要旨 : Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target ... Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors. 履歴 登録 2020年10月11日 登録サイト : PDBJ / 処理サイト : PDBJ改定 1.0 2021年1月27日 Provider : repository / タイプ : Initial release改定 1.1 2021年2月3日 Group : Database references / カテゴリ : citationItem : _citation.journal_volume / _citation.page_first ... _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
すべて表示 表示を減らす