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Yorodumi- PDB-9o3y: Human 80S ribosome bound to IDB-002 stalled on FPAK-containing na... -
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Open data
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Basic information
| Entry | Database: PDB / ID: 9o3y | |||||||||||||||||||||||||||||||||
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| Title | Human 80S ribosome bound to IDB-002 stalled on FPAK-containing nascent chain | |||||||||||||||||||||||||||||||||
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Keywords | TRANSLATION / translation inhibitor / interdictor / ribosome / cryogenic-electron microscopy (cryo-EM) / ribotoxic stress response / cancer / MYC | |||||||||||||||||||||||||||||||||
| Function / homology | Function and homology informationembryonic brain development / translation at presynapse / exit from mitosis / optic nerve development / response to insecticide / regulation of translation involved in cellular response to UV / eukaryotic 80S initiation complex / negative regulation of formation of translation preinitiation complex / axial mesoderm development / negative regulation of endoplasmic reticulum unfolded protein response ...embryonic brain development / translation at presynapse / exit from mitosis / optic nerve development / response to insecticide / regulation of translation involved in cellular response to UV / eukaryotic 80S initiation complex / negative regulation of formation of translation preinitiation complex / axial mesoderm development / negative regulation of endoplasmic reticulum unfolded protein response / ribosomal protein import into nucleus / regulation of G1 to G0 transition / retinal ganglion cell axon guidance / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / positive regulation of ubiquitin-protein transferase activity / protein-DNA complex disassembly / positive regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of gastrulation / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / protein tyrosine kinase inhibitor activity / 90S preribosome assembly / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / nucleolus organization / positive regulation of DNA-templated transcription initiation / alpha-beta T cell differentiation / TNFR1-mediated ceramide production / positive regulation of DNA damage response, signal transduction by p53 class mediator / GAIT complex / negative regulation of RNA splicing / TORC2 complex binding / neural crest cell differentiation / supercoiled DNA binding / NF-kappaB complex / negative regulation of DNA repair / G1 to G0 transition / cytoplasmic translational initiation / oxidized purine DNA binding / cysteine-type endopeptidase activator activity involved in apoptotic process / middle ear morphogenesis / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / rRNA modification in the nucleus and cytosol / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / Formation of the ternary complex, and subsequently, the 43S complex / ion channel inhibitor activity / laminin receptor activity / protein kinase A binding / homeostatic process / pigmentation / Ribosomal scanning and start codon recognition / positive regulation of mitochondrial depolarization / Translation initiation complex formation / macrophage chemotaxis / lung morphogenesis / negative regulation of Wnt signaling pathway / positive regulation of natural killer cell proliferation / fibroblast growth factor binding / monocyte chemotaxis / BH3 domain binding / Protein hydroxylation / negative regulation of translational frameshifting / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of GTPase activity / TOR signaling / SARS-CoV-1 modulates host translation machinery / mTORC1-mediated signalling / iron-sulfur cluster binding / regulation of cell division / Peptide chain elongation / cellular response to ethanol / Selenocysteine synthesis / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Formation of a pool of free 40S subunits / negative regulation of protein binding / protein serine/threonine kinase inhibitor activity / Eukaryotic Translation Termination / blastocyst development / ubiquitin ligase inhibitor activity / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency / negative regulation of respiratory burst involved in inflammatory response / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Viral mRNA Translation / positive regulation of signal transduction by p53 class mediator / protein localization to nucleus / negative regulation of ubiquitin-dependent protein catabolic process / 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 / protein targeting / Major pathway of rRNA processing in the nucleolus and cytosol / regulation of translational fidelity Similarity search - Function | |||||||||||||||||||||||||||||||||
| Biological species | Homo sapiens (human) | |||||||||||||||||||||||||||||||||
| Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.2 Å | |||||||||||||||||||||||||||||||||
Authors | Sauer, P.V. / Schuller, A.P. / Hamann, L.G. | |||||||||||||||||||||||||||||||||
| Funding support | 1items
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Citation | Journal: Nat Commun / Year: 2026Title: Context-dependent translation inhibition as a cancer therapeutic modality. Authors: Paige D Diamond / Paul V Sauer / Mikael Holm / Canessa J Swanson-Swett / Lucas Ferguson / Natalie M Bratset / Grant W Wienker / Justin Seiwert Sim / Hailey K Adams / Lillian Kenner / Margot ...Authors: Paige D Diamond / Paul V Sauer / Mikael Holm / Canessa J Swanson-Swett / Lucas Ferguson / Natalie M Bratset / Grant W Wienker / Justin Seiwert Sim / Hailey K Adams / Lillian Kenner / Margot Meyers / David Gygi / Zef A Könst / Sogole Sami Bahmanyar / Lawrence G Hamann / Anthony P Schuller / ![]() Abstract: Recent work has demonstrated that some bacterial antibiotics that inhibit protein synthesis by binding the peptidyl transferase center (PTC) of the ribosome act in a context-dependent manner, ...Recent work has demonstrated that some bacterial antibiotics that inhibit protein synthesis by binding the peptidyl transferase center (PTC) of the ribosome act in a context-dependent manner, inhibiting translation elongation only at specific amino acids. However, this phenomenon has yet to be documented for compounds that inhibit the PTC of the human ribosome. Here, we use structure-based design to guide the synthesis of such PTC-binding, context-dependent inhibitors of the human ribosome, termed interdictors. In the PTC, these compounds preferentially interact with nascent protein residues that exhibit complementary physiochemical properties to the moieties of the small molecule, causing structural rearrangements in both the nascent polypeptide chain and ribosomal RNA. Further, the compounds differentially impact ribosome surveillance pathways, including the ribotoxic stress response. Finally, we confirm their anti-tumor activity after oral dosing in a mouse xenograft model of triple-negative breast cancer. Together, our data establish targeting oncogenic dependency factors through context-dependent inhibition of translation as a potential small molecule therapeutic modality for historically difficult to address cancers. | |||||||||||||||||||||||||||||||||
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Structure visualization
| Structure viewer | Molecule: Molmil Jmol/JSmol |
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Downloads & links
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Download
| PDBx/mmCIF format | 9o3y.cif.gz | 5.6 MB | Display | PDBx/mmCIF format |
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| PDB format | pdb9o3y.ent.gz | Display | PDB format | |
| PDBx/mmJSON format | 9o3y.json.gz | Tree view | PDBx/mmJSON format | |
| Others | Other downloads |
-Validation report
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/o3/9o3y ftp://data.pdbj.org/pub/pdb/validation_reports/o3/9o3y | HTTPS FTP |
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-Related structure data
| Related structure data | ![]() 70086MC ![]() 9o3vC ![]() 9o3wC ![]() 70085 M: map data used to model this data C: citing same article ( |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
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Assembly
| Deposited unit | ![]()
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Components
-RNA chain , 6 types, 6 molecules L5L7L8PtS2mR
| #1: RNA chain | Mass: 1640884.500 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
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| #2: RNA chain | Mass: 38691.914 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 23898 |
| #3: RNA chain | Mass: 50171.703 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 555853 |
| #47: RNA chain | Mass: 24492.529 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
| #48: RNA chain | Mass: 603580.125 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
| #82: RNA chain | Mass: 958.660 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
-60S ribosomal protein ... , 3 types, 3 molecules LALFLa
| #4: Protein | Mass: 28088.863 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62917 |
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| #9: Protein | Mass: 29290.973 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P18124 |
| #29: Protein | Mass: 16604.535 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P46776 |
+Large ribosomal subunit protein ... , 37 types, 37 molecules LBLCLDLELGLHLILJLLLMLNLOLPLQLRLSLTLULVLWLXLYLZLbLcLdLeLfLgLh...
-Ubiquitin-ribosomal protein ... , 2 types, 2 molecules LmSf
| #41: Protein | Mass: 14800.474 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62987 |
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| #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 |
+Small ribosomal subunit protein ... , 29 types, 29 molecules LnSASBSCSDSESFSGSHSISJSKSLSMSNSOSPSQSRSSSTSUSWSXSZSaSbScSd
-Protein/peptide , 1 types, 1 molecules NC
| #46: Protein/peptide | Mass: 1568.924 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: FLAG-VHP-FPAK fusion peptide: DYKDDDDKDYKDDDDKDYKDDDDKGSLSDEDFKAVFGMTRSAFANLPLWKQQNLKKEKGLFGSTEAMINTERDICTWASHERETESTINGFPAK Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
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-40S ribosomal protein ... , 2 types, 2 molecules SVSY
| #70: Protein | Mass: 9150.427 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P63220 |
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| #73: Protein | Mass: 15463.333 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62847 |
-Protein , 2 types, 2 molecules SeSg
| #79: Protein | Mass: 14415.724 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62861 |
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| #81: Protein | Mass: 35115.652 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P63244 |
-Non-polymers , 8 types, 10471 molecules 












| #83: Chemical | ChemComp-K / #84: Chemical | ChemComp-SPD / #85: Chemical | ChemComp-PUT / #86: Chemical | #87: Chemical | ChemComp-MG / #88: Chemical | ChemComp-A1B76 / ( | Mass: 374.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23FN2O4 / Feature type: SUBJECT OF INVESTIGATION #89: Chemical | ChemComp-ZN / #90: Water | ChemComp-HOH / | |
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-Details
| Has ligand of interest | Y |
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| Has protein modification | Y |
| Sequence details | The full sequence of the Nascent chain is ...The full sequence of the Nascent chain is DYKDDDDKDY |
-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 ribosome bound to IDB-001 stalled on MYC nascent chain Type: RIBOSOME / Entity ID: #1-#44, #46-#48, #50-#82 / Source: NATURAL |
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| Molecular weight | Value: 4.3 MDa / Experimental value: NO |
| Source (natural) | Organism: Homo sapiens (human) |
| Buffer solution | pH: 7.5 Details: 20mM Tris, 100mM KOAc, 7.5mM MgOAc, 0.25mM Spermidine, 2mM DTT, 0.05% w/v b-OG, 50uM IDB-001 |
| Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
| Specimen support | Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1 |
| Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 292 K |
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Electron microscopy imaging
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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| Microscopy | Model: TFS KRIOS |
| Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
| Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 900 nm |
| Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
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| CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||
| 3D reconstruction | Resolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 263989 / Symmetry type: POINT |
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