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Open data
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Basic information
| Entry | Database: PDB / ID: 9o3v | |||||||||||||||||||||||||||||||||
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| Title | Human 80S ribosome stalled on MYC nascent chain | |||||||||||||||||||||||||||||||||
Components |
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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 / response to insecticide / regulation of translation involved in cellular response to UV / eukaryotic 80S initiation complex / ribosomal protein import into nucleus / negative regulation of endoplasmic reticulum unfolded protein response / regulation of G1 to G0 transition / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / oxidized pyrimidine DNA binding ...embryonic brain development / translation at presynapse / response to insecticide / regulation of translation involved in cellular response to UV / eukaryotic 80S initiation complex / ribosomal protein import into nucleus / negative regulation of endoplasmic reticulum unfolded protein response / regulation of G1 to G0 transition / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / protein-DNA complex disassembly / 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 / protein tyrosine kinase inhibitor activity / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / nucleolus organization / TNFR1-mediated ceramide production / negative regulation of formation of translation preinitiation complex / positive regulation of DNA damage response, signal transduction by p53 class mediator / positive regulation of ubiquitin-protein transferase activity / GAIT complex / positive regulation of DNA-templated transcription initiation / negative regulation of RNA splicing / negative regulation of DNA repair / TORC2 complex binding / G1 to G0 transition / Enterobacterial factors antagonize host defense / PD-L1(CD274) glycosylation and translocation to plasma membrane / erythrocyte homeostasis / supercoiled DNA binding / regulation of establishment of cell polarity / cysteine-type endopeptidase activator activity involved in apoptotic process / oxidized purine DNA binding / NF-kappaB complex / cytoplasmic translational initiation / rRNA modification in the nucleus and cytosol / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / negative regulation of phagocytosis / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / cytoplasmic side of rough endoplasmic reticulum membrane / Formation of the ternary complex, and subsequently, the 43S complex / laminin receptor activity / negative regulation of myoblast fusion / ion channel inhibitor activity / protein kinase A binding / positive regulation of mitochondrial depolarization / Ribosomal scanning and start codon recognition / PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA / Translation initiation complex formation / Dengue Virus Genome Translation and Replication / Maturation of DENV proteins / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA / Protein hydroxylation / TOR signaling / BH3 domain binding / negative regulation of translational frameshifting / iron-sulfur cluster binding / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / monocyte chemotaxis / mTORC1-mediated signalling / SARS-CoV-1 modulates host translation machinery / regulation of cell division / positive regulation of GTPase activity / Peptide chain elongation / cellular response to ethanol / Selenocysteine synthesis / Formation of a pool of free 40S subunits / protein targeting / negative regulation of protein binding / negative regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Eukaryotic Translation Termination / protein serine/threonine kinase inhibitor activity / protein localization to nucleus / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency / AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274) / negative regulation of ubiquitin-dependent protein catabolic process / ubiquitin ligase inhibitor activity / Viral mRNA Translation / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / positive regulation of signal transduction by p53 class mediator / GTP hydrolysis and joining of the 60S ribosomal subunit / embryo implantation / L13a-mediated translational silencing of Ceruloplasmin expression / Major pathway of rRNA processing in the nucleolus and cytosol / GSK3B-mediated proteasomal degradation of PD-L1(CD274) / regulation of translational fidelity / positive regulation of microtubule polymerization / SPOP-mediated proteasomal degradation of PD-L1(CD274) / phagocytic cup / maturation of LSU-rRNA 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 | 9o3v.cif.gz | 5.5 MB | Display | PDBx/mmCIF format |
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| PDB format | pdb9o3v.ent.gz | Display | PDB format | |
| PDBx/mmJSON format | 9o3v.json.gz | Tree view | PDBx/mmJSON format | |
| Others | Other downloads |
-Validation report
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/o3/9o3v ftp://data.pdbj.org/pub/pdb/validation_reports/o3/9o3v | HTTPS FTP |
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-Related structure data
| Related structure data | ![]() 70083MC ![]() 9o3wC ![]() 9o3yC 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: 24136.328 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: 268011.844 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: 1884.049 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: fusion protein FLAG-VHP-MYC: DYKDDDDKDYKDDDDKDYKDDDDKGSLSDEDFKAVFGMTRSAFANLPLWKQQNLKKEKGLFGSSPQGSPEPLVLHEETPPTTSSDSEEEQEDE 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 , 7 types, 5278 molecules 












| #83: Chemical | ChemComp-MG / #84: Chemical | ChemComp-K / #85: Chemical | ChemComp-SPD / #86: Chemical | ChemComp-PUT / #87: Chemical | #88: Chemical | ChemComp-ZN / #89: Water | ChemComp-HOH / | |
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-Details
| Has ligand of interest | N |
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| Has protein modification | Y |
| Sequence details | The full sequence of Nascent chain is ...The full sequence of Nascent chain is SAWSHPQFEK |
-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 stalled on MYC peptide, generated by IVTT Type: RIBOSOME / Entity ID: #46, #1-#44, #47-#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 |
| Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
| Specimen support | 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: 171177 / Symmetry type: POINT |
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