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Yorodumi- PDB-6xa1: Structure of a drug-like compound stalled human translation termi... -
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Basic information
| Entry | Database: PDB / ID: 6xa1 | |||||||||
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| Title | Structure of a drug-like compound stalled human translation termination complex | |||||||||
Components |
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Keywords | RIBOSOME / Selectively stalling / translation termination / drug-like compound / human ribosome | |||||||||
| Function / homology | Function and homology informationtranslation termination factor activity / translation release factor complex / cytoplasmic translational termination / regulation of translational termination / protein methylation / translation release factor activity, codon specific / translation release factor activity / exit from mitosis / optic nerve development / response to insecticide ...translation termination factor activity / translation release factor complex / cytoplasmic translational termination / regulation of translational termination / protein methylation / translation release factor activity, codon specific / translation release factor activity / exit from mitosis / optic nerve development / response to insecticide / eukaryotic 80S initiation complex / negative regulation of protein neddylation / regulation of translation involved in cellular response to UV / sequence-specific mRNA binding / axial mesoderm development / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / retinal ganglion cell axon guidance / oxidized pyrimidine DNA binding / response to TNF agonist / negative regulation of endoplasmic reticulum unfolded protein response / positive regulation of base-excision repair / ribosomal protein import into nucleus / 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 intrinsic apoptotic signaling pathway in response to DNA damage / peptidyl-tRNA hydrolase activity / positive regulation of gastrulation / 90S preribosome assembly / protein tyrosine kinase inhibitor activity / positive regulation of endodeoxyribonuclease activity / nucleolus organization / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / TNFR1-mediated ceramide production / negative regulation of DNA repair / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / negative regulation of RNA splicing / GAIT complex / positive regulation of DNA damage response, signal transduction by p53 class mediator / TORC2 complex binding / G1 to G0 transition / supercoiled DNA binding / NF-kappaB complex / neural crest cell differentiation / oxidized purine DNA binding / cysteine-type endopeptidase activator activity involved in apoptotic process / middle ear morphogenesis / positive regulation of ubiquitin-protein transferase activity / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / negative regulation of bicellular tight junction assembly / regulation of establishment of cell polarity / ubiquitin-like protein conjugating enzyme binding / rRNA modification in the nucleus and cytosol / negative regulation of phagocytosis / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / cytoplasmic side of rough endoplasmic reticulum membrane / negative regulation of ubiquitin protein ligase activity / protein kinase A binding / laminin receptor activity / homeostatic process / ion channel inhibitor activity / Ribosomal scanning and start codon recognition / pigmentation / Translation initiation complex formation / positive regulation of mitochondrial depolarization / macrophage chemotaxis / lung morphogenesis / positive regulation of T cell receptor signaling pathway / fibroblast growth factor binding / negative regulation of Wnt signaling pathway / positive regulation of natural killer cell proliferation / male meiosis I / monocyte chemotaxis / TOR signaling / negative regulation of translational frameshifting / BH3 domain binding / positive regulation of activated T cell proliferation / Protein hydroxylation / SARS-CoV-1 modulates host translation machinery / iron-sulfur cluster binding / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of cell division / cellular response to ethanol / 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 / cellular response to actinomycin D / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Eukaryotic Translation Termination / blastocyst development / positive regulation of GTPase activity / negative regulation of ubiquitin-dependent protein catabolic process / protein serine/threonine kinase inhibitor activity / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency Similarity search - Function | |||||||||
| Biological species | Homo sapiens (human) | |||||||||
| Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
Authors | Li, W. / Cate, J. | |||||||||
| Funding support | United States, 2items
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Citation | Journal: Nat Commun / Year: 2020Title: Selective inhibition of human translation termination by a drug-like compound. Authors: Wenfei Li / Stacey Tsai-Lan Chang / Fred R Ward / Jamie H D Cate / ![]() Abstract: Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among ...Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies. | |||||||||
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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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Download
| PDBx/mmCIF format | 6xa1.cif.gz | 4.6 MB | Display | PDBx/mmCIF format |
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| PDB format | pdb6xa1.ent.gz | Display | PDB format | |
| PDBx/mmJSON format | 6xa1.json.gz | Tree view | PDBx/mmJSON format | |
| Others | Other downloads |
-Validation report
| Summary document | 6xa1_validation.pdf.gz | 2.2 MB | Display | wwPDB validaton report |
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| Full document | 6xa1_full_validation.pdf.gz | 2.6 MB | Display | |
| Data in XML | 6xa1_validation.xml.gz | 387.5 KB | Display | |
| Data in CIF | 6xa1_validation.cif.gz | 648.8 KB | Display | |
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xa/6xa1 ftp://data.pdbj.org/pub/pdb/validation_reports/xa/6xa1 | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 22085MC M: map data used to model this data C: citing same article ( |
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| Similar structure data |
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Links
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Assembly
| Deposited unit | ![]()
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Components
+60S ribosomal protein ... , 41 types, 41 molecules LALBLCLDLELFLGLHLILJLLLMLNLOLPLQLRLSLTLVLWLXLYLZLaLbLcLdLeLf...
-RNA chain , 6 types, 6 molecules L5L7L8S2Bvk
| #3: RNA chain | Mass: 1138224.750 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: 28SrRNA with PF846 / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
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| #4: RNA chain | Mass: 38691.914 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: GenBank: 23898 |
| #5: RNA chain | Mass: 49852.496 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
| #46: RNA chain | Mass: 514092.625 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
| #80: RNA chain | Mass: 24641.777 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
| #82: RNA chain | Mass: 4047.445 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
-Protein , 3 types, 3 molecules LUSgj
| #23: Protein | Mass: 11722.535 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: Q7Z4W8 |
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| #67: Protein | Mass: 34669.113 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RACK1, GNB2L1, HLC7, PIG21 / Production host: Homo sapiens (human) / References: UniProt: P63244 |
| #81: Protein | Mass: 46149.758 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ETF1, ERF1, RF1, SUP45L1 / Production host: Homo sapiens (human) / References: UniProt: P62495 |
+40S ribosomal protein ... , 32 types, 32 molecules SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSbSeSf
-Protein/peptide , 1 types, 1 molecules NC
| #83: Protein/peptide | Mass: 2523.151 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
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-Non-polymers , 4 types, 201 molecules 






| #84: Chemical | ChemComp-MG / #85: Chemical | ChemComp-MVM / | #86: Chemical | ChemComp-ZN / #87: Chemical | |
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-Details
| Has ligand of interest | Y |
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| Has protein modification | Y |
-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: Drug-like compound-stalled translation termination complex Type: RIBOSOME / Entity ID: #1-#83 / Source: RECOMBINANT |
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| Source (natural) | Organism: Homo sapiens (human) |
| Source (recombinant) | Organism: Homo sapiens (human) |
| Buffer solution | pH: 7.6 |
| Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
| Specimen support | Details: unspecified |
| Vitrification | Cryogen name: ETHANE |
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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: FLOOD BEAM |
| Electron lens | Mode: BRIGHT FIELD |
| Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
| CTF correction | Type: NONE |
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| 3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 57324 / Symmetry type: POINT |
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Homo sapiens (human)
United States, 2items
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