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Yorodumi- EMDB-22085: Selectively stalling of translation termination by a drug-like co... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-22085 | |||||||||
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Title | Selectively stalling of translation termination by a drug-like compound | |||||||||
Map data | Overall refined map after applying B factor of -40. | |||||||||
Sample |
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Function / homology | Function and homology information translation termination factor activity / translation release factor complex / cytoplasmic translational termination / translation release factor activity / regulation of translational termination / eukaryotic 80S initiation complex / negative regulation of protein neddylation / translation release factor activity, codon specific / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response ...translation termination factor activity / translation release factor complex / cytoplasmic translational termination / translation release factor activity / regulation of translational termination / eukaryotic 80S initiation complex / negative regulation of protein neddylation / translation release factor activity, codon specific / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / protein tyrosine kinase inhibitor activity / axial mesoderm development / protein methylation / positive regulation of respiratory burst involved in inflammatory response / ribosomal protein import into nucleus / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of formation of translation preinitiation complex / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / nucleolus organization / IRE1-RACK1-PP2A complex / 90S preribosome assembly / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / TORC2 complex binding / sequence-specific mRNA binding / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / oxidized purine DNA binding / supercoiled DNA binding / neural crest cell differentiation / middle ear morphogenesis / NF-kappaB complex / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / aminoacyl-tRNA hydrolase activity / positive regulation of ubiquitin-protein transferase activity / rRNA modification in the nucleus and cytosol / A band / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / regulation of G1 to G0 transition / laminin receptor activity / exit from mitosis / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / 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 / protein kinase A binding / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / 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 / pigmentation / retinal ganglion cell axon guidance / positive regulation of mitochondrial depolarization / mammalian oogenesis stage / G1 to G0 transition / homeostatic process / activation-induced cell death of T cells / macrophage chemotaxis / negative regulation of Wnt signaling pathway / lung morphogenesis / positive regulation of T cell receptor signaling pathway / fibroblast growth factor binding / positive regulation of activated T cell proliferation / male meiosis I / iron-sulfur cluster binding / regulation of cell division / Protein hydroxylation / monocyte chemotaxis / 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 / Eukaryotic Translation Termination / phagocytic cup / blastocyst development / ubiquitin ligase inhibitor activity / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / negative regulation of respiratory burst involved in inflammatory response / cyclin binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
Authors | Li W / Cate J / Ward RF / Chang S | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Nat Commun / Year: 2020 Title: 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. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_22085.map.gz | 277.9 MB | EMDB map data format | |
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Header (meta data) | emd-22085-v30.xml emd-22085.xml | 21 KB 21 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_22085_fsc.xml | 15.1 KB | Display | FSC data file |
Images | emd_22085.png | 173.4 KB | ||
Others | emd_22085_additional_1.map.gz emd_22085_additional_2.map.gz emd_22085_additional_3.map.gz emd_22085_additional_4.map.gz emd_22085_half_map_1.map.gz emd_22085_half_map_2.map.gz | 240.7 MB 277.8 MB 240.7 MB 240.9 MB 241.8 MB 241.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-22085 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-22085 | HTTPS FTP |
-Validation report
Summary document | emd_22085_validation.pdf.gz | 526 KB | Display | EMDB validaton report |
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Full document | emd_22085_full_validation.pdf.gz | 525.5 KB | Display | |
Data in XML | emd_22085_validation.xml.gz | 20.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22085 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22085 | HTTPS FTP |
-Related structure data
Related structure data | 6xa1MC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_22085.map.gz / Format: CCP4 / Size: 303.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Overall refined map after applying B factor of -40. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.15 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: masked refinement for 60S before sharpen.ing
File | emd_22085_additional_1.map | ||||||||||||
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Annotation | masked refinement for 60S before sharpen.ing | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: masked refinement for 60S eRF1 tRNA before sharpening.
File | emd_22085_additional_2.map | ||||||||||||
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Annotation | masked refinement for 60S_eRF1_tRNA before sharpening. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: masked refinement for 40S eRF1 tRNA before sharpening.
File | emd_22085_additional_3.map | ||||||||||||
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Annotation | masked refinement for 40S_eRF1_tRNA before sharpening. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Overall refined map before sharpening .
File | emd_22085_additional_4.map | ||||||||||||
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Annotation | Overall refined map before sharpening . | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map of PF846-stalled termination complex after overall...
File | emd_22085_half_map_1.map | ||||||||||||
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Annotation | Half map of PF846-stalled termination complex after overall refinement. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map of PF846-stalled termination complex after overall...
File | emd_22085_half_map_2.map | ||||||||||||
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Annotation | Half map of PF846-stalled termination complex after overall refinement. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Translation termination complex stalled by a drug-like compound
Entire | Name: Translation termination complex stalled by a drug-like compound |
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Components |
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-Supramolecule #1: Translation termination complex stalled by a drug-like compound
Supramolecule | Name: Translation termination complex stalled by a drug-like compound type: complex / ID: 1 / Parent: 0 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.6 |
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Grid | Details: unspecified |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Overall B value: 50 |
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Output model | PDB-6xa1: |