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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 / cytoplasmic translational termination / translation release factor complex / regulation of translational termination / translation release factor activity / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / translation release factor activity, codon specific / protein methylation / oxidized pyrimidine DNA binding ...translation termination factor activity / cytoplasmic translational termination / translation release factor complex / regulation of translational termination / translation release factor activity / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / translation release factor activity, codon specific / protein methylation / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / eukaryotic 80S initiation complex / protein tyrosine kinase inhibitor activity / negative regulation of protein neddylation / 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 / axial mesoderm development / regulation of G1 to G0 transition / negative regulation of formation of translation preinitiation complex / IRE1-RACK1-PP2A complex / nucleolus organization / ribosomal protein import into nucleus / 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 / : / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / exit from mitosis / protein-DNA complex disassembly / TNFR1-mediated ceramide production / 90S preribosome assembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of RNA splicing / negative regulation of DNA repair / laminin receptor activity / optic nerve development / TORC2 complex binding / oxidized purine DNA binding / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / supercoiled DNA binding / GAIT complex / G1 to G0 transition / neural crest cell differentiation / sequence-specific mRNA binding / rRNA modification in the nucleus and cytosol / retinal ganglion cell axon guidance / negative regulation of phagocytosis / NF-kappaB complex / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / positive regulation of ubiquitin-protein transferase activity / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / aminoacyl-tRNA hydrolase activity / A band / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / pigmentation / protein kinase A binding / negative regulation of ubiquitin protein ligase activity / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / Translation initiation complex formation / phagocytic cup / positive regulation of mitochondrial depolarization / response to aldosterone / negative regulation of Wnt signaling pathway / homeostatic process / positive regulation of T cell receptor signaling pathway / lung morphogenesis / macrophage chemotaxis / positive regulation of activated T cell proliferation / fibroblast growth factor binding / regulation of cell division / SARS-CoV-1 modulates host translation machinery / Protein hydroxylation / iron-sulfur cluster binding / male meiosis I / TOR signaling / BH3 domain binding / mTORC1-mediated signalling / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Peptide chain elongation / Selenocysteine synthesis / protein-RNA complex assembly / monocyte chemotaxis / cysteine-type endopeptidase activator activity involved in apoptotic process / Formation of a pool of free 40S subunits / ribosomal small subunit export from nucleus / positive regulation of cyclic-nucleotide phosphodiesterase activity / Eukaryotic Translation Termination / blastocyst development / Response of EIF2AK4 (GCN2) to amino acid deficiency / translation regulator activity 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 |
-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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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2 |
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: |