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Yorodumi- PDB-5lks: Structure-function insights reveal the human ribosome as a cancer... -
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Basic information
| Entry | Database: PDB / ID: 5lks | |||||||||||||||||||||||||||||||||||||||
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| Title | Structure-function insights reveal the human ribosome as a cancer target for antibiotics | |||||||||||||||||||||||||||||||||||||||
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Keywords | RIBOSOME / CryoEM / human ribosome / 80S / cycloheximide | |||||||||||||||||||||||||||||||||||||||
| Function / homology | Function and homology informationtranslation at presynapse / exit from mitosis / eukaryotic 80S initiation complex / negative regulation of protein neddylation / optic nerve development / response to insecticide / regulation of translation involved in cellular response to UV / oxidized pyrimidine DNA binding / response to TNF agonist / negative regulation of endoplasmic reticulum unfolded protein response ...translation at presynapse / exit from mitosis / eukaryotic 80S initiation complex / negative regulation of protein neddylation / optic nerve development / response to insecticide / regulation of translation involved in cellular response to UV / oxidized pyrimidine DNA binding / response to TNF agonist / negative regulation of endoplasmic reticulum unfolded protein response / positive regulation of base-excision repair / axial mesoderm development / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / positive regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / ribosomal protein import into nucleus / positive regulation of gastrulation / protein tyrosine kinase inhibitor activity / protein-DNA complex disassembly / IRE1-RACK1-PP2A complex / 90S preribosome assembly / 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 / supercoiled DNA binding / TORC2 complex binding / alpha-beta T cell differentiation / neural crest cell differentiation / G1 to G0 transition / NF-kappaB complex / cysteine-type endopeptidase activator activity involved in apoptotic process / oxidized purine DNA binding / positive regulation of ubiquitin-protein transferase activity / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / regulation of establishment of cell polarity / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / 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 / Ribosomal scanning and start codon recognition / pigmentation / homeostatic process / Translation initiation complex formation / positive regulation of mitochondrial depolarization / macrophage chemotaxis / positive regulation of T cell receptor signaling pathway / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / lung morphogenesis / male meiosis I / monocyte chemotaxis / positive regulation of activated T cell proliferation / positive regulation of natural killer cell proliferation / negative regulation of translational frameshifting / TOR signaling / Protein hydroxylation / BH3 domain binding / SARS-CoV-1 modulates host translation machinery / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to ethanol / regulation of cell division / iron-sulfur cluster binding / mTORC1-mediated signalling / Peptide chain elongation / Selenocysteine synthesis / Formation of a pool of free 40S subunits / 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) / Eukaryotic Translation Termination / ubiquitin ligase inhibitor activity / positive regulation of GTPase activity / cellular response to actinomycin D / blastocyst development / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / negative regulation of ubiquitin-dependent protein catabolic process / positive regulation of signal transduction by p53 class mediator / protein serine/threonine kinase inhibitor activity / Viral mRNA Translation / negative regulation of respiratory burst involved in inflammatory response / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / protein localization to nucleus / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression Similarity search - Function | |||||||||||||||||||||||||||||||||||||||
| Biological species | Homo sapiens (human) | |||||||||||||||||||||||||||||||||||||||
| Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||||||||||||||||||||||||||||||||
Authors | Myasnikov, A.G. / Natchiar, S.K. / Nebout, M. / Hazemann, I. / Imbert, V. / Khatter, H. / Peyron, J.-F. / Klaholz, B.P. | |||||||||||||||||||||||||||||||||||||||
Citation | Journal: Nat Commun / Year: 2016Title: Structure-function insights reveal the human ribosome as a cancer target for antibiotics. Authors: Alexander G Myasnikov / S Kundhavai Natchiar / Marielle Nebout / Isabelle Hazemann / Véronique Imbert / Heena Khatter / Jean-François Peyron / Bruno P Klaholz / ![]() Abstract: 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: Journal: Nature / Year: 2015Title: Structure of the human 80S ribosome. Authors: Heena Khatter / Alexander G Myasnikov / S Kundhavai Natchiar / Bruno P Klaholz / ![]() Abstract: 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. | |||||||||||||||||||||||||||||||||||||||
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Structure visualization
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| Structure viewer | Molecule: Molmil Jmol/JSmol |
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Downloads & links
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| PDBx/mmCIF format | 5lks.cif.gz | 5.3 MB | Display | PDBx/mmCIF format |
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| PDB format | pdb5lks.ent.gz | Display | PDB format | |
| PDBx/mmJSON format | 5lks.json.gz | Tree view | PDBx/mmJSON format | |
| Others | Other downloads |
-Validation report
| Summary document | 5lks_validation.pdf.gz | 1.7 MB | Display | wwPDB validaton report |
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| Full document | 5lks_full_validation.pdf.gz | 3.5 MB | Display | |
| Data in XML | 5lks_validation.xml.gz | 639.9 KB | Display | |
| Data in CIF | 5lks_validation.cif.gz | 973.3 KB | Display | |
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/lk/5lks ftp://data.pdbj.org/pub/pdb/validation_reports/lk/5lks | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 4070MC M: map data used to model this data C: citing same article ( |
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| Similar structure data |
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Assembly
| Deposited unit | ![]()
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Components
-RNA chain , 4 types, 4 molecules L5L7L8S2
| #1: RNA chain | Mass: 1640238.125 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 86475748 |
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| #2: RNA chain | Mass: 38998.078 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 23898 |
| #3: RNA chain | Mass: 50449.812 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 555853 |
| #47: RNA chain | Mass: 602752.875 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 36162 |
+60S ribosomal protein ... , 41 types, 41 molecules LALBLCLDLELFLGLHLILJLLLMLNLOLPLQLRLSLTLULVLWLXLYLZLaLcLdLeLf...
-Ribosomal protein ... , 2 types, 2 molecules LbSe
| #30: Protein | Mass: 17604.018 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: A0A024R326 |
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| #79: Protein | Mass: 14415.724 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
-Protein , 3 types, 3 molecules LmSgSf
| #41: Protein | Mass: 14758.394 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62987 |
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| #68: Protein | Mass: 35115.652 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P63244 |
| #80: Protein | Mass: 18004.041 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62979 |
+40S ribosomal protein ... , 30 types, 30 molecules SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSb
-Non-polymers , 4 types, 264 molecules 






| #81: Chemical | ChemComp-3HE / | ||||
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| #82: Chemical | ChemComp-MG / #83: Chemical | ChemComp-ZN / #84: Water | ChemComp-HOH / | |
-Details
| Has protein modification | N |
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-Experimental details
-Experiment
| Experiment | Method: ELECTRON MICROSCOPY |
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| EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
| Component | Name: Human 80S ribsome / Type: RIBOSOME / Entity ID: #1-#80 / Source: NATURAL |
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| Source (natural) | Organism: Homo sapiens (human) |
| Buffer solution | pH: 7.5 |
| Specimen | Conc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
| Specimen support | Grid material: COPPER/RHODIUM / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2 |
| Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K |
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Electron microscopy imaging
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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| Microscopy | Model: FEI TITAN KRIOS |
| Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN |
| Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 79000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 400 nm / Calibrated defocus min: 500 nm / Calibrated defocus max: 3000 nm / Cs: 0.001 mm / C2 aperture diameter: 50 µm |
| Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 105 K / Temperature (min): 79 K |
| Image recording | Average exposure time: 1 sec. / Electron dose: 50 e/Å2 / Detector mode: OTHER / Film or detector model: FEI FALCON II (4k x 4k) / Num. of grids imaged: 4 / Num. of real images: 6600 |
| EM imaging optics | Spherical aberration corrector: CS corrected microscope |
| Image scans | Sampling size: 14 µm / Movie frames/image: 7 / Used frames/image: 3-9 |
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Processing
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| CTF correction | Details: Relion / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
| 3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 19000 / Algorithm: FOURIER SPACE / Details: RELION / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||
| Atomic model building | Protocol: RIGID BODY FIT / Target criteria: Maximum likelihood |
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