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基本情報
登録情報 | データベース: PDB / ID: 5lks | ||||||||||||||||||||||||||||||||||||
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タイトル | Structure-function insights reveal the human ribosome as a cancer target for antibiotics | ||||||||||||||||||||||||||||||||||||
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![]() | RIBOSOME / CryoEM / human ribosome / 80S / cycloheximide | ||||||||||||||||||||||||||||||||||||
機能・相同性 | ![]() translation at presynapse / exit from mitosis / male meiosis I / eukaryotic 80S initiation complex / negative regulation of protein neddylation / optic nerve development / response to insecticide / negative regulation of endoplasmic reticulum unfolded protein response / regulation of translation involved in cellular response to UV / oxidized pyrimidine DNA binding ...translation at presynapse / exit from mitosis / male meiosis I / eukaryotic 80S initiation complex / negative regulation of protein neddylation / optic nerve development / 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 / 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 / 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 / alpha-beta T cell differentiation / neural crest cell differentiation / G1 to G0 transition / NF-kappaB complex / 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 / negative regulation of ubiquitin-dependent protein catabolic process / protein serine/threonine kinase inhibitor activity / Viral mRNA Translation / negative regulation of respiratory burst involved in inflammatory response / Maturation of protein E / Maturation of protein E / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / protein localization to nucleus 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: 3.6 Å | ||||||||||||||||||||||||||||||||||||
![]() | Myasnikov, A.G. / Natchiar, S.K. / Nebout, M. / Hazemann, I. / Imbert, V. / Khatter, H. / Peyron, J.-F. / Klaholz, B.P. | ||||||||||||||||||||||||||||||||||||
![]() | ![]() タイトル: Structure-function insights reveal the human ribosome as a cancer target for antibiotics. 著者: Alexander G Myasnikov / S Kundhavai Natchiar / Marielle Nebout / Isabelle Hazemann / Véronique Imbert / Heena Khatter / Jean-François Peyron / Bruno P Klaholz / ![]() 要旨: Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis ...Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target. #1: ![]() タイトル: Structure of the human 80S ribosome. 著者: Heena Khatter / Alexander G Myasnikov / S Kundhavai Natchiar / Bruno P Klaholz / ![]() 要旨: Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has ...Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRNA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal subunits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis. | ||||||||||||||||||||||||||||||||||||
履歴 |
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構造の表示
ムービー |
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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 | ![]() | 5.3 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 | ![]() | 1.4 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.5 MB | 表示 | |
XML形式データ | ![]() | 316.6 KB | 表示 | |
CIF形式データ | ![]() | 583.1 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
-RNA鎖 , 4種, 4分子 L5L7L8S2
#1: RNA鎖 | 分子量: 1640238.125 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
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#2: RNA鎖 | 分子量: 38998.078 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
#3: RNA鎖 | 分子量: 50449.812 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
#47: RNA鎖 | 分子量: 602752.875 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
+60S ribosomal protein ... , 41種, 41分子 LALBLCLDLELFLGLHLILJLLLMLNLOLPLQLRLSLTLULVLWLXLYLZLaLcLdLeLf...
-Ribosomal protein ... , 2種, 2分子 LbSe
#30: タンパク質 | 分子量: 17604.018 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
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#79: タンパク質 | 分子量: 14415.724 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
-タンパク質 , 3種, 3分子 LmSgSf
#41: タンパク質 | 分子量: 14758.394 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
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#68: タンパク質 | 分子量: 35115.652 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
#80: タンパク質 | 分子量: 18004.041 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() |
+40S ribosomal protein ... , 30種, 30分子 SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSb
-非ポリマー , 4種, 264分子 






#81: 化合物 | ChemComp-3HE / | ||||
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#82: 化合物 | ChemComp-MG / #83: 化合物 | ChemComp-ZN / #84: 水 | ChemComp-HOH / | |
-詳細
Has protein modification | 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 |
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試料調製
構成要素 | 名称: Human 80S ribsome / タイプ: RIBOSOME / Entity ID: #1-#80 / 由来: NATURAL |
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由来(天然) | 生物種: ![]() |
緩衝液 | pH: 7.5 |
試料 | 濃度: 0.5 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: COPPER/RHODIUM / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil R2/2 |
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: 283 K |
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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 / 倍率(公称値): 79000 X / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 400 nm / Calibrated defocus min: 500 nm / 最大 デフォーカス(補正後): 3000 nm / Cs: 0.001 mm / C2レンズ絞り径: 50 µm |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER 最高温度: 105 K / 最低温度: 79 K |
撮影 | 平均露光時間: 1 sec. / 電子線照射量: 50 e/Å2 / 検出モード: OTHER フィルム・検出器のモデル: FEI FALCON II (4k x 4k) 撮影したグリッド数: 4 / 実像数: 6600 |
電子光学装置 | 球面収差補正装置: CS corrected microscope |
画像スキャン | サンプリングサイズ: 14 µm / 動画フレーム数/画像: 7 / 利用したフレーム数/画像: 3-9 |
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解析
EMソフトウェア |
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CTF補正 | 詳細: Relion / タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 19000 / アルゴリズム: FOURIER SPACE / 詳細: RELION / クラス平均像の数: 1 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: RIGID BODY FIT / Target criteria: Maximum likelihood |