+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-30614 | |||||||||
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タイトル | CryoEM structure of human gamma-secretase in complex with E2012 and L685458 | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | inhibitor / modulator / membrane protein / HYDROLASE | |||||||||
機能・相同性 | 機能・相同性情報 Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / 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 / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of amyloid precursor protein biosynthetic process / protein catabolic process at postsynapse / Noncanonical activation of NOTCH3 / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / central nervous system myelination / synaptic vesicle targeting / negative regulation of axonogenesis / membrane protein intracellular domain proteolysis / regulation of resting membrane potential / choline transport / T cell activation involved in immune response / skin morphogenesis / NOTCH4 Activation and Transmission of Signal to the Nucleus / growth factor receptor binding / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / myeloid dendritic cell differentiation / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / endoplasmic reticulum calcium ion homeostasis / metanephros development / regulation of phosphorylation / locomotion / brain morphogenesis / nuclear outer membrane / amyloid precursor protein metabolic process / skeletal system morphogenesis / myeloid cell homeostasis / smooth endoplasmic reticulum calcium ion homeostasis / regulation of long-term synaptic potentiation / astrocyte activation involved in immune response / regulation of canonical Wnt signaling pathway / embryonic limb morphogenesis / aggresome / cell fate specification / glutamate receptor signaling pathway / ciliary rootlet / azurophil granule membrane / regulation of postsynapse organization / G protein-coupled dopamine receptor signaling pathway / Golgi cisterna membrane / positive regulation of amyloid fibril formation / mitochondrial transport / 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 dendritic spine development / positive regulation of receptor recycling / adult behavior / blood vessel development / regulation of neuron projection development / heart looping / amyloid precursor protein catabolic process / cerebral cortex cell migration / protein glycosylation / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / endopeptidase activator activity / autophagosome assembly / EPH-ephrin mediated repulsion of cells / neuron development / somitogenesis / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / negative regulation of ubiquitin-dependent protein catabolic process / calcium ion homeostasis / Nuclear signaling by ERBB4 / T cell proliferation / rough endoplasmic reticulum / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / Degradation of the extracellular matrix / post-embryonic development / positive regulation of glycolytic process / NRIF signals cell death from the nucleus / cellular response to calcium ion / Activated NOTCH1 Transmits Signal to the Nucleus / negative regulation of protein phosphorylation / cerebellum development / thymus development / epithelial cell proliferation / apoptotic signaling pathway / dendritic shaft / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / PDZ domain binding / neuron migration 類似検索 - 分子機能 | |||||||||
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: 2.6 Å | |||||||||
データ登録者 | Yang G / Zhou R | |||||||||
資金援助 | 中国, 1件
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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 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_30614.map.gz | 117 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-30614-v30.xml emd-30614.xml | 15.5 KB 15.5 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_30614.png | 50 KB | ||
Filedesc metadata | emd-30614.cif.gz | 6.6 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-30614 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-30614 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_30614_validation.pdf.gz | 564.3 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_30614_full_validation.pdf.gz | 563.9 KB | 表示 | |
XML形式データ | emd_30614_validation.xml.gz | 6.5 KB | 表示 | |
CIF形式データ | emd_30614_validation.cif.gz | 7.5 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30614 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30614 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_30614.map.gz / 形式: CCP4 / 大きさ: 125 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.0825 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-試料の構成要素
+全体 : human gamma-secretase
+超分子 #1: human gamma-secretase
+分子 #1: Nicastrin
+分子 #2: Presenilin-1
+分子 #3: Gamma-secretase subunit APH-1A
+分子 #4: Gamma-secretase subunit PEN-2
+分子 #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
+分子 #8: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+分子 #9: 1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazo...
+分子 #10: PHOSPHATIDYLETHANOLAMINE
+分子 #11: ~{tert}-butyl ~{N}-[(2~{S},3~{R},5~{R})-6-[[(2~{S})-1-[[(2~{S})-1...
+分子 #12: CHOLESTEROL
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.4 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 1.5625 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: EMDB MAP |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 234427 |
初期 角度割当 | タイプ: PROJECTION MATCHING |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |