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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: 6xa1 | |||||||||
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| タイトル | Structure of a drug-like compound stalled human translation termination complex | |||||||||
要素 |
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キーワード | RIBOSOME / Selectively stalling / translation termination / drug-like compound / human ribosome | |||||||||
| 機能・相同性 | 機能・相同性情報translation termination factor activity / translation release factor complex / cytoplasmic translational termination / regulation of translational termination / translation release factor activity / translation release factor activity, codon specific / protein methylation / exit from mitosis / optic nerve development / response to insecticide ...translation termination factor activity / translation release factor complex / cytoplasmic translational termination / regulation of translational termination / translation release factor activity / translation release factor activity, codon specific / protein methylation / exit from mitosis / optic nerve development / response to insecticide / sequence-specific mRNA binding / regulation of translation involved in cellular response to UV / eukaryotic 80S initiation complex / negative regulation of formation of translation preinitiation complex / axial mesoderm development / negative regulation of endoplasmic reticulum unfolded protein response / ribosomal protein import into nucleus / regulation of G1 to G0 transition / retinal ganglion cell axon guidance / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / protein-DNA complex disassembly / positive regulation of ubiquitin-protein transferase activity / positive regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of gastrulation / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / protein tyrosine kinase inhibitor activity / 90S preribosome assembly / peptidyl-tRNA hydrolase activity / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / nucleolus organization / positive regulation of DNA-templated transcription initiation / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / TNFR1-mediated ceramide production / positive regulation of DNA damage response, signal transduction by p53 class mediator / GAIT complex / negative regulation of RNA splicing / TORC2 complex binding / neural crest cell differentiation / supercoiled DNA binding / NF-kappaB complex / negative regulation of DNA repair / G1 to G0 transition / cytoplasmic translational initiation / oxidized purine DNA binding / cysteine-type endopeptidase activator activity involved in apoptotic process / middle ear morphogenesis / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / rRNA modification in the nucleus and cytosol / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / protein kinase A binding / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / laminin receptor activity / Translation initiation complex formation / homeostatic process / pigmentation / positive regulation of mitochondrial depolarization / macrophage chemotaxis / lung morphogenesis / negative regulation of Wnt signaling pathway / positive regulation of natural killer cell proliferation / fibroblast growth factor binding / male meiosis I / monocyte chemotaxis / BH3 domain binding / Protein hydroxylation / negative regulation of translational frameshifting / SARS-CoV-1 modulates host translation machinery / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / TOR signaling / positive regulation of GTPase activity / iron-sulfur cluster binding / mTORC1-mediated signalling / Peptide chain elongation / regulation of cell division / Selenocysteine synthesis / Formation of a pool of free 40S subunits / cellular response to ethanol / blastocyst development / Eukaryotic Translation Termination / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency / negative regulation of protein binding / protein serine/threonine kinase inhibitor activity / Viral mRNA Translation / ubiquitin ligase inhibitor activity / negative regulation of respiratory burst involved in inflammatory response / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) 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: 2.8 Å | |||||||||
データ登録者 | Li, W. / Cate, J. | |||||||||
| 資金援助 | 米国, 2件
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引用 | ジャーナル: Nat Commun / 年: 2020タイトル: Selective inhibition of human translation termination by a drug-like compound. 著者: Wenfei Li / Stacey Tsai-Lan Chang / Fred R Ward / Jamie H D Cate / ![]() 要旨: Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among ...Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies. | |||||||||
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構造の表示
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| 構造ビューア | 分子: Molmil Jmol/JSmol |
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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 | 6xa1.cif.gz | 4.6 MB | 表示 | PDBx/mmCIF形式 |
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| PDB形式 | pdb6xa1.ent.gz | 表示 | PDB形式 | |
| PDBx/mmJSON形式 | 6xa1.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
| アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/xa/6xa1 ftp://data.pdbj.org/pub/pdb/validation_reports/xa/6xa1 | HTTPS FTP |
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-関連構造データ
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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
+60S ribosomal protein ... , 41種, 41分子 LALBLCLDLELFLGLHLILJLLLMLNLOLPLQLRLSLTLVLWLXLYLZLaLbLcLdLeLf...
-RNA鎖 , 6種, 6分子 L5L7L8S2Bvk
| #3: RNA鎖 | 分子量: 1138224.750 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: 28SrRNA with PF846 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) |
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| #4: RNA鎖 | 分子量: 38691.914 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) / 参照: GenBank: 23898 |
| #5: RNA鎖 | 分子量: 49852.496 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) |
| #46: RNA鎖 | 分子量: 514092.625 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) |
| #80: RNA鎖 | 分子量: 24641.777 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) |
| #82: RNA鎖 | 分子量: 4047.445 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) |
-タンパク質 , 3種, 3分子 LUSgj
| #23: タンパク質 | 分子量: 11722.535 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q7Z4W8 |
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| #67: タンパク質 | 分子量: 34669.113 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: RACK1, GNB2L1, HLC7, PIG21 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P63244 |
| #81: タンパク質 | 分子量: 46149.758 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: ETF1, ERF1, RF1, SUP45L1 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P62495 |
+40S ribosomal protein ... , 32種, 32分子 SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSbSeSf
-タンパク質・ペプチド , 1種, 1分子 NC
| #83: タンパク質・ペプチド | 分子量: 2523.151 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト) |
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-非ポリマー , 4種, 201分子 






| #84: 化合物 | ChemComp-MG / #85: 化合物 | ChemComp-MVM / | #86: 化合物 | ChemComp-ZN / #87: 化合物 | |
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-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: Drug-like compound-stalled translation termination complex タイプ: RIBOSOME / Entity ID: #1-#83 / 由来: RECOMBINANT |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 由来(組換発現) | 生物種: Homo sapiens (ヒト) |
| 緩衝液 | pH: 7.6 |
| 試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
| 試料支持 | 詳細: unspecified |
| 急速凍結 | 凍結剤: ETHANE |
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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: FEI TITAN KRIOS |
| 電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 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) |
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解析
| CTF補正 | タイプ: NONE |
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| 3次元再構成 | 解像度: 2.8 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 57324 / 対称性のタイプ: POINT |
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コントローラー
万見について




Homo sapiens (ヒト)
米国, 2件
引用
UCSF Chimera











PDBj





















































