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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 | ||||||
Components |
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Keywords | RIBOSOME / CryoEM / human ribosome / 80S / cycloheximide | ||||||
Function / homology | Function and homology information eukaryotic 80S initiation complex / negative regulation of protein neddylation / translation at presynapse / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / protein tyrosine kinase inhibitor activity / axial mesoderm development / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair ...eukaryotic 80S initiation complex / negative regulation of protein neddylation / translation at presynapse / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / protein tyrosine kinase inhibitor activity / axial mesoderm development / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / ribosomal protein import into nucleus / positive regulation of respiratory burst involved in inflammatory response / negative regulation of formation of translation preinitiation complex / nucleolus organization / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / 90S preribosome assembly / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / positive regulation of endodeoxyribonuclease activity / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / supercoiled DNA binding / neural crest cell differentiation / oxidized purine DNA binding / NF-kappaB complex / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / negative regulation of phagocytosis / regulation of establishment of cell polarity / positive regulation of ubiquitin-protein transferase activity / A band / rRNA modification in the nucleus and cytosol / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / alpha-beta T cell differentiation / cytoplasmic side of rough endoplasmic reticulum membrane / regulation of G1 to G0 transition / exit from mitosis / laminin receptor activity / pigmentation / 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 / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / protein kinase A binding / optic nerve development / negative regulation of ubiquitin protein ligase activity / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / response to aldosterone / Translation initiation complex formation / retinal ganglion cell axon guidance / positive regulation of mitochondrial depolarization / mammalian oogenesis stage / homeostatic process / G1 to G0 transition / activation-induced cell death of T cells / lung morphogenesis / positive regulation of T cell receptor signaling pathway / macrophage chemotaxis / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / iron-sulfur cluster binding / monocyte chemotaxis / positive regulation of activated T cell proliferation / male meiosis I / Protein hydroxylation / regulation of cell division / negative regulation of peptidyl-serine phosphorylation / 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 / cysteine-type endopeptidase activator activity involved in apoptotic process / Selenocysteine synthesis / positive regulation of signal transduction by p53 class mediator / Formation of a pool of free 40S subunits / blastocyst development / phagocytic cup / Eukaryotic Translation Termination / ubiquitin ligase inhibitor activity / negative regulation of respiratory burst involved in inflammatory response / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein localization to nucleus / Viral mRNA Translation / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / TOR signaling / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / T cell proliferation involved in immune response / regulation of translational fidelity 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: 2016 Title: 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: 2015 Title: 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. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
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 | 1.3 MB | Display | wwPDB validaton report |
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Full document | 5lks_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 5lks_validation.xml.gz | 322.5 KB | Display | |
Data in CIF | 5lks_validation.cif.gz | 583.4 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 (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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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 / | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-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 |
-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 |
-Processing
EM software |
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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 |