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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 9nb9 | ||||||
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タイトル | Viral protein DP71L in complex with phosphorylated eIF2alpha (NTD) and protein phosphatase 1A (D64A), stabilized by G-actin/DNAseI | ||||||
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![]() | TRANSLATION / Phosphatase / complex / ISR | ||||||
機能・相同性 | ![]() regulation of macromolecule metabolic process / regulation of neutrophil mediated cytotoxicity / regulation of primary metabolic process / zymogen granule / regulation of acute inflammatory response / protein serine/threonine phosphatase inhibitor activity / regulation of glycogen catabolic process / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot ...regulation of macromolecule metabolic process / regulation of neutrophil mediated cytotoxicity / regulation of primary metabolic process / zymogen granule / regulation of acute inflammatory response / protein serine/threonine phosphatase inhibitor activity / regulation of glycogen catabolic process / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / HRI-mediated signaling / deoxyribonuclease I / Cellular response to mitochondrial stress / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / PTW/PP1 phosphatase complex / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / protein phosphatase type 1 complex / PERK regulates gene expression / response to kainic acid / glycogen granule / eukaryotic translation initiation factor 2 complex / deoxyribonuclease I activity / symbiont-mediated suppression of host translation initiation / protein phosphatase 1 binding / neutrophil activation involved in immune response / cadherin binding involved in cell-cell adhesion / regulation of translational initiation in response to stress / eukaryotic 48S preinitiation complex / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / DNA catabolic process / histone H2AXS139 phosphatase activity / RNA polymerase II CTD heptapeptide repeat Y1 phosphatase activity / RNA polymerase II CTD heptapeptide repeat T4 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MAP kinase serine/threonine phosphatase activity / myosin phosphatase activity / regulation of canonical Wnt signaling pathway / calmodulin-dependent protein phosphatase activity / dephosphorylation / Formation of the ternary complex, and subsequently, the 43S complex / cytoskeletal motor activator activity / glycogen metabolic process / branching morphogenesis of an epithelial tube / Ribosomal scanning and start codon recognition / myosin heavy chain binding / protein-serine/threonine phosphatase / Translation initiation complex formation / protein serine/threonine phosphatase activity / tropomyosin binding / Triglyceride catabolism / entrainment of circadian clock by photoperiod / Maturation of hRSV A proteins / troponin I binding / filamentous actin / mesenchyme migration / phosphatase activity / actin filament bundle / telomere maintenance in response to DNA damage / actin filament bundle assembly / phosphoprotein phosphatase activity / skeletal muscle myofibril / striated muscle thin filament / skeletal muscle thin filament assembly / actin monomer binding / Response of EIF2AK4 (GCN2) to amino acid deficiency / DARPP-32 events / transition metal ion binding / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / positive regulation of glycogen biosynthetic process / ribonucleoprotein complex binding / protein dephosphorylation / mitophagy / skeletal muscle fiber development / stress fiber / titin binding / actin filament polymerization / translation initiation factor activity / stress granule assembly / cellular response to amino acid starvation / response to endoplasmic reticulum stress / Downregulation of TGF-beta receptor signaling / filopodium / actin filament / adherens junction / translational initiation / lung development / circadian regulation of gene expression / response to lead ion / regulation of circadian rhythm / PKR-mediated signaling / ABC-family proteins mediated transport / 加水分解酵素; 酸無水物に作用; 酸無水物に作用・細胞または細胞小器官の運動に関与 / cytoplasmic stress granule 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: 3.03 Å | ||||||
![]() | Reineke, L.C. / Dalwadi, U. / Croll, T. / Arthur, C. / Lee, D.J. / Frost, A. / Costa-Mattioli, M. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction. 要旨: The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts ...The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions-including Down syndrome, Alzheimer's disease and aging-but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies. | ||||||
履歴 |
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 312.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 193.8 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 879.4 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 885.7 KB | 表示 | |
XML形式データ | ![]() | 34.6 KB | 表示 | |
CIF形式データ | ![]() | 56.1 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 49223MC C: 同じ文献を引用 ( M: このデータのモデリングに利用したマップデータ |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-タンパク質 , 5種, 5分子 BCDEA
#1: タンパク質 | 分子量: 8435.730 Da / 分子数: 1 / 由来タイプ: 組換発現 由来: (組換発現) ![]() ![]() 遺伝子: Pret-172 / 発現宿主: ![]() ![]() |
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#2: タンパク質 | 分子量: 37514.039 Da / 分子数: 1 / Mutation: D64A / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() 参照: UniProt: P62136, protein-serine/threonine phosphatase |
#3: タンパク質 | 分子量: 42096.953 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() ![]() |
#4: タンパク質 | 分子量: 31374.436 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() ![]() |
#5: タンパク質 | 分子量: 21817.863 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
-非ポリマー , 3種, 3分子 




#6: 化合物 | ChemComp-MN / |
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#7: 化合物 | ChemComp-CA / |
#8: 化合物 | ChemComp-ATP / |
-詳細
研究の焦点であるリガンドがあるか | Y |
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Has protein modification | Y |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha (2-187) タイプ: COMPLEX / Entity ID: #1-#5 / 由来: MULTIPLE SOURCES | |||||||||||||||||||||||||||||||||||
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分子量 | 値: 0.14 MDa / 実験値: NO | |||||||||||||||||||||||||||||||||||
由来(天然) | 生物種: ![]() | |||||||||||||||||||||||||||||||||||
由来(組換発現) | 生物種: ![]() ![]() | |||||||||||||||||||||||||||||||||||
緩衝液 | pH: 7.5 | |||||||||||||||||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 5.5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | |||||||||||||||||||||||||||||||||||
試料支持 | グリッドの材料: GOLD / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 | |||||||||||||||||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 278 K / 詳細: 3.5 uL volume, -5 blot force, 1.5 blot time |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: TFS KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 130000 X / 最大 デフォーカス(公称値): 1800 nm / 最小 デフォーカス(公称値): 800 nm / Cs: 2.7 mm / アライメント法: COMA FREE |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: TFS FALCON 4i (4k x 4k) 撮影したグリッド数: 1 / 実像数: 5236 |
電子光学装置 | エネルギーフィルター名称: TFS Selectris X / エネルギーフィルタースリット幅: 10 eV |
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解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 1315944 | ||||||||||||||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.03 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 309745 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | Source name: AlphaFold / タイプ: in silico model | ||||||||||||||||||||||||||||||||||||||||||||||||
拘束条件 |
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