+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7d44 | |||||||||
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タイトル | eIF2B-eIF2(aP), aP2 complex | |||||||||
要素 |
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キーワード | TRANSLATION / Complex / Translational control | |||||||||
機能・相同性 | 機能・相同性情報 regulation of translation in response to endoplasmic reticulum stress / translation initiation ternary complex / glial limiting end-foot / response to kainic acid / Cellular response to mitochondrial stress / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / eukaryotic translation initiation factor 2B complex / negative regulation of translational initiation in response to stress / Response of EIF2AK1 (HRI) to heme deficiency ...regulation of translation in response to endoplasmic reticulum stress / translation initiation ternary complex / glial limiting end-foot / response to kainic acid / Cellular response to mitochondrial stress / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / eukaryotic translation initiation factor 2B complex / negative regulation of translational initiation in response to stress / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / PERK-mediated unfolded protein response / PERK regulates gene expression / eukaryotic translation initiation factor 2 complex / regulation of translational initiation in response to stress / cytoplasmic translational initiation / oligodendrocyte development / guanyl-nucleotide exchange factor complex / astrocyte development / eukaryotic 48S preinitiation complex / astrocyte differentiation / Formation of the ternary complex, and subsequently, the 43S complex / regulation of translational initiation / Translation initiation complex formation / Ribosomal scanning and start codon recognition / Response of EIF2AK4 (GCN2) to amino acid deficiency / L13a-mediated translational silencing of Ceruloplasmin expression / GTP hydrolysis and joining of the 60S ribosomal subunit / positive regulation of translational initiation / response to glucose / stress granule assembly / ovarian follicle development / translation initiation factor binding / translational initiation / translation initiation factor activity / cellular response to amino acid starvation / myelination / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / ABC-family proteins mediated transport / PKR-mediated signaling / response to peptide hormone / cytoplasmic stress granule / cellular response to UV / ribosome binding / regulation of translation / T cell receptor signaling pathway / cellular response to heat / cellular response to oxidative stress / response to heat / positive regulation of apoptotic process / synapse / GTP binding / RNA binding / extracellular exosome / ATP binding / membrane / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能 | |||||||||
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: 4 Å | |||||||||
データ登録者 | Kashiwagi, K. / Ito, T. | |||||||||
資金援助 | 日本, 2件
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引用 | ジャーナル: Mol Cell / 年: 2021 タイトル: ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. 著者: Alisa F Zyryanova / Kazuhiro Kashiwagi / Claudia Rato / Heather P Harding / Ana Crespillo-Casado / Luke A Perera / Ayako Sakamoto / Madoka Nishimoto / Mayumi Yonemochi / Mikako Shirouzu / ...著者: Alisa F Zyryanova / Kazuhiro Kashiwagi / Claudia Rato / Heather P Harding / Ana Crespillo-Casado / Luke A Perera / Ayako Sakamoto / Madoka Nishimoto / Mayumi Yonemochi / Mikako Shirouzu / Takuhiro Ito / David Ron / 要旨: The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in ...The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR. | |||||||||
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 | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7d44.cif.gz | 646 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7d44.ent.gz | 527.9 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7d44.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 7d44_validation.pdf.gz | 785.5 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7d44_full_validation.pdf.gz | 876.2 KB | 表示 | |
XML形式データ | 7d44_validation.xml.gz | 104 KB | 表示 | |
CIF形式データ | 7d44_validation.cif.gz | 162.9 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/d4/7d44 ftp://data.pdbj.org/pub/pdb/validation_reports/d4/7d44 | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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-要素
-Translation initiation factor eIF-2B subunit ... , 5種, 10分子 ABCDEFGHIJ
#1: タンパク質 | 分子量: 33754.148 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EIF2B1, EIF2BA / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: Q14232 #2: タンパク質 | 分子量: 39039.547 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EIF2B2, EIF2BB / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: P49770 #3: タンパク質 | 分子量: 50304.230 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EIF2B3 / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: Q9NR50 #4: タンパク質 | 分子量: 57640.168 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EIF2B4, EIF2BD / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: Q9UI10 #5: タンパク質 | 分子量: 80466.609 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EIF2B5, EIF2BE / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: Q13144 |
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-タンパク質 , 1種, 2分子 KL
#6: タンパク質 | 分子量: 36241.156 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EIF2S1, EIF2A / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P05198 |
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-詳細
研究の焦点であるリガンドがあるか | N |
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-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 |
-試料調製
構成要素 |
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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.5 | ||||||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Talos Arctica / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TECNAI ARCTICA |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 200 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.17.1_3660: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING ONLY | ||||||||||||||||||||||||
3次元再構成 | 解像度: 4 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 80921 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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