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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 | |||||||||
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![]() | RIBOSOME / Selectively stalling / translation termination / drug-like compound / human ribosome | |||||||||
機能・相同性 | ![]() translation termination factor activity / translation release factor complex / cytoplasmic translational termination / regulation of translational termination / translation release factor activity, codon specific / protein methylation / exit from mitosis / male meiosis I / eukaryotic 80S initiation complex / negative regulation of protein neddylation ...translation termination factor activity / translation release factor complex / cytoplasmic translational termination / regulation of translational termination / translation release factor activity, codon specific / protein methylation / exit from mitosis / male meiosis I / eukaryotic 80S initiation complex / negative regulation of protein neddylation / optic nerve development / translation release factor activity / response to insecticide / negative regulation of endoplasmic reticulum unfolded protein response / regulation of translation involved in cellular response to UV / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / axial mesoderm development / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / ribosomal protein import into nucleus / positive regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / 90S preribosome assembly / protein tyrosine kinase inhibitor activity / protein-DNA complex disassembly / IRE1-RACK1-PP2A complex / positive regulation of endodeoxyribonuclease activity / nucleolus organization / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / sequence-specific mRNA binding / positive regulation of Golgi to plasma membrane protein transport / retinal ganglion cell axon guidance / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / GAIT complex / peptidyl-tRNA hydrolase activity / positive regulation of DNA damage response, signal transduction by p53 class mediator / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / supercoiled DNA binding / TORC2 complex binding / neural crest cell differentiation / G1 to G0 transition / NF-kappaB complex / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / positive regulation of ubiquitin-protein transferase activity / cysteine-type endopeptidase activator activity involved in apoptotic process / oxidized purine DNA binding / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / ubiquitin-like protein conjugating enzyme binding / negative regulation of bicellular tight junction assembly / regulation of establishment of cell polarity / middle ear morphogenesis / negative regulation of phagocytosis / rRNA modification in the nucleus and cytosol / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / laminin receptor activity / negative regulation of ubiquitin protein ligase activity / protein kinase A binding / ion channel inhibitor activity / pigmentation / Ribosomal scanning and start codon recognition / homeostatic process / Translation initiation complex formation / positive regulation of mitochondrial depolarization / macrophage chemotaxis / positive regulation of T cell receptor signaling pathway / fibroblast growth factor binding / negative regulation of Wnt signaling pathway / lung morphogenesis / monocyte chemotaxis / positive regulation of activated T cell proliferation / positive regulation of natural killer cell proliferation / negative regulation of translational frameshifting / Protein hydroxylation / TOR signaling / BH3 domain binding / SARS-CoV-1 modulates host translation machinery / regulation of cell division / mTORC1-mediated signalling / cellular response to ethanol / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / iron-sulfur cluster binding / Peptide chain elongation / Selenocysteine synthesis / Formation of a pool of free 40S subunits / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Eukaryotic Translation Termination / ubiquitin ligase inhibitor activity / blastocyst development / positive regulation of GTPase activity / cellular response to actinomycin D / Response of EIF2AK4 (GCN2) to amino acid deficiency / positive regulation of signal transduction by p53 class mediator / SRP-dependent cotranslational protein targeting to membrane 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: 2.8 Å | |||||||||
![]() | Li, W. / Cate, J. | |||||||||
資金援助 | ![]()
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![]() | ![]() 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: ![]() ![]() |
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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 | ![]() | 4.6 MB | 表示 | ![]() |
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PDB形式 | ![]() | 表示 | ![]() | |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 2.2 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 2.6 MB | 表示 | |
XML形式データ | ![]() | 387.5 KB | 表示 | |
CIF形式データ | ![]() | 648.8 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-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) ![]() ![]() |
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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) ![]() ![]() |
#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) ![]() ![]() |
#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) ![]() ![]() |
#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) ![]() ![]() |
#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) ![]() ![]() |
-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) ![]() ![]() |
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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) ![]() ![]() |
#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) ![]() ![]() |
+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) ![]() ![]() |
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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: ![]() |
由来(組換発現) | 生物種: ![]() |
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: ![]() |
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 |