+データを開く
-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 | ||||||
要素 |
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キーワード | RIBOSOME (リボソーム) / CryoEM (低温電子顕微鏡法) / human ribosome (リボソーム) / 80S / cycloheximide (シクロヘキシミド) | ||||||
機能・相同性 | 機能・相同性情報 positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / eukaryotic 80S initiation complex / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of protein neddylation / protein tyrosine kinase inhibitor activity / translation at presynapse / axial mesoderm development ...positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / eukaryotic 80S initiation complex / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of protein neddylation / protein tyrosine kinase inhibitor activity / translation at presynapse / axial mesoderm development / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of respiratory burst involved in inflammatory response / positive regulation of gastrulation / regulation of G1 to G0 transition / negative regulation of formation of translation preinitiation complex / ribosomal protein import into nucleus / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / IRE1-RACK1-PP2A complex / nucleolus organization / : / exit from mitosis / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / protein-DNA complex disassembly / 90S preribosome assembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / TNFR1-mediated ceramide production / negative regulation of RNA splicing / negative regulation of DNA repair / laminin receptor activity / optic nerve development / TORC2 complex binding / oxidized purine DNA binding / GAIT complex / G1 to G0 transition / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / supercoiled DNA binding / neural crest cell differentiation / retinal ganglion cell axon guidance / middle ear morphogenesis / negative regulation of phagocytosis / NF-kappaB complex / rRNA modification in the nucleus and cytosol / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / positive regulation of ubiquitin-protein transferase activity / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / A band / positive regulation of signal transduction by p53 class mediator / alpha-beta T cell differentiation / ubiquitin ligase inhibitor activity / 顔料 / protein kinase A binding / Ribosomal scanning and start codon recognition / negative regulation of ubiquitin protein ligase activity / ion channel inhibitor activity / Translation initiation complex formation / phagocytic cup / positive regulation of mitochondrial depolarization / response to aldosterone / homeostatic process / negative regulation of Wnt signaling pathway / lung morphogenesis / macrophage chemotaxis / positive regulation of T cell receptor signaling pathway / fibroblast growth factor binding / positive regulation of activated T cell proliferation / regulation of cell division / ヒドロキシル化 / male meiosis I / MTOR / iron-sulfur cluster binding / BH3 domain binding / mTORC1-mediated signalling / SARS-CoV-1 modulates host translation machinery / Peptide chain elongation / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Selenocysteine synthesis / protein-RNA complex assembly / monocyte chemotaxis / Formation of a pool of free 40S subunits / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of cyclic-nucleotide phosphodiesterase activity / Eukaryotic Translation Termination / ribosomal small subunit export from nucleus / blastocyst development / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / translation regulator activity / Viral mRNA Translation / protein localization to nucleus / cellular response to actinomycin D / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / GTP hydrolysis and joining of the 60S ribosomal subunit / negative regulation of respiratory burst involved in inflammatory response 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: 3.6 Å | ||||||
データ登録者 | Myasnikov, A.G. / Natchiar, S.K. / Nebout, M. / Hazemann, I. / Imbert, V. / Khatter, H. / Peyron, J.-F. / Klaholz, B.P. | ||||||
引用 | ジャーナル: Nat Commun / 年: 2016 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: ジャーナル: Nature / 年: 2015 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 |
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 | 5lks.cif.gz | 5.3 MB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb5lks.ent.gz | 表示 | PDB形式 | |
PDBx/mmJSON形式 | 5lks.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/lk/5lks ftp://data.pdbj.org/pub/pdb/validation_reports/lk/5lks | HTTPS FTP |
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-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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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) Homo sapiens (ヒト) / 参照: GenBank: 86475748 |
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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) Homo sapiens (ヒト) / 参照: GenBank: 23898 |
#3: RNA鎖 | 分子量: 50449.812 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 参照: GenBank: 555853 |
#47: RNA鎖 | 分子量: 602752.875 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 参照: GenBank: 36162 |
+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) Homo sapiens (ヒト) / 参照: UniProt: A0A024R326 |
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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) Homo sapiens (ヒト) |
-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) Homo sapiens (ヒト) / 参照: UniProt: P62987 |
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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) Homo sapiens (ヒト) / 参照: UniProt: P63244 |
#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) Homo sapiens (ヒト) / 参照: UniProt: P62979 |
+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 / | |
-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 | 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: Homo sapiens (ヒト) |
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 |
-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: SPOT SCAN |
電子レンズ | モード: BRIGHT FIELDBright-field microscopy / 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: その他 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 |
-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 |