+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40344 | ||||||||||||
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Title | Terminating ribosome with SRI-41315 | ||||||||||||
Map data | unsharpened map | ||||||||||||
Sample |
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Keywords | termination / SRI-41315 / RIBOSOME | ||||||||||||
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 / translation release factor activity, codon specific / protein methylation / sequence-specific mRNA binding / aminoacyl-tRNA hydrolase activity / regulation of G1 to G0 transition ...translation termination factor activity / translation release factor complex / cytoplasmic translational termination / translation release factor activity / regulation of translational termination / translation release factor activity, codon specific / protein methylation / sequence-specific mRNA binding / aminoacyl-tRNA hydrolase activity / 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 / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / optic nerve development / retinal ganglion cell axon guidance / mammalian oogenesis stage / G1 to G0 transition / activation-induced cell death of T cells / Protein hydroxylation / positive regulation of signal transduction by p53 class mediator / Eukaryotic Translation Termination / phagocytic cup / ubiquitin ligase inhibitor activity / ribosomal small subunit binding / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / TOR signaling / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / 90S preribosome / T cell proliferation involved in immune response / protein-RNA complex assembly / erythrocyte development / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / negative regulation of ubiquitin-dependent protein catabolic process / ribosomal subunit export from nucleus / translation regulator activity / cellular response to actinomycin D / ribosomal small subunit export from nucleus / translational termination / cytosolic ribosome / laminin binding / endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / rough endoplasmic reticulum / gastrulation / MDM2/MDM4 family protein binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / maturation of LSU-rRNA / class I DNA-(apurinic or apyrimidinic site) endonuclease activity / DNA-(apurinic or apyrimidinic site) lyase / rescue of stalled ribosome / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / positive regulation of apoptotic signaling pathway / maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / ribosomal large subunit biogenesis / cellular response to leukemia inhibitory factor / maturation of SSU-rRNA / placenta development / small-subunit processome / positive regulation of translation / translational initiation / protein kinase C binding / positive regulation of protein-containing complex assembly / G1/S transition of mitotic cell cycle / cellular response to gamma radiation / transcription coactivator binding / mRNA 5'-UTR binding / Regulation of expression of SLITs and ROBOs / modification-dependent protein catabolic process / spindle / cytoplasmic ribonucleoprotein granule / positive regulation of canonical Wnt signaling pathway / rhythmic process / rRNA processing / protein tag activity / antimicrobial humoral immune response mediated by antimicrobial peptide / glucose homeostasis / virus receptor activity / ribosome biogenesis / ribosome binding / retina development in camera-type eye / regulation of translation / heparin binding / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / small ribosomal subunit rRNA binding / cell body / T cell differentiation in thymus / 5S rRNA binding / large ribosomal subunit rRNA binding / cytosolic small ribosomal subunit / perikaryon / defense response to Gram-negative bacterium / cytosolic large ribosomal subunit / killing of cells of another organism / cytoplasmic translation / cell differentiation Similarity search - Function | ||||||||||||
Biological species | Oryctolagus cuniculus (rabbit) / Homo sapiens (human) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.5 Å | ||||||||||||
Authors | Yip MCJ / Coelho JPL / Oltion K / Tauton J / Shao S | ||||||||||||
Funding support | United States, 3 items
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Citation | Journal: Nat Chem Biol / Year: 2024 Title: The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center. Authors: João P L Coelho / Matthew C J Yip / Keely Oltion / Jack Taunton / Sichen Shao / Abstract: Translation termination is an essential cellular process, which is also of therapeutic interest for diseases that manifest from premature stop codons. In eukaryotes, translation termination requires ...Translation termination is an essential cellular process, which is also of therapeutic interest for diseases that manifest from premature stop codons. In eukaryotes, translation termination requires eRF1, which recognizes stop codons, catalyzes the release of nascent proteins from ribosomes and facilitates ribosome recycling. The small molecule SRI-41315 triggers eRF1 degradation and enhances translational readthrough of premature stop codons. However, the mechanism of action of SRI-41315 on eRF1 and translation is not known. Here we report cryo-EM structures showing that SRI-41315 acts as a metal-dependent molecular glue between the N domain of eRF1 responsible for stop codon recognition and the ribosomal subunit interface near the decoding center. Retention of eRF1 on ribosomes by SRI-41315 leads to ribosome collisions, eRF1 ubiquitylation and a higher frequency of translation termination at near-cognate stop codons. Our findings reveal a new mechanism of release factor inhibition and additional implications for pharmacologically targeting eRF1. | ||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40344.map.gz | 335.9 MB | EMDB map data format | |
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Header (meta data) | emd-40344-v30.xml emd-40344.xml | 110.8 KB 110.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_40344_fsc.xml | 16.9 KB | Display | FSC data file |
Images | emd_40344.png | 150.7 KB | ||
Filedesc metadata | emd-40344.cif.gz | 22.3 KB | ||
Others | emd_40344_additional_1.map.gz emd_40344_additional_2.map.gz emd_40344_half_map_1.map.gz emd_40344_half_map_2.map.gz | 101.1 MB 356.6 MB 337.3 MB 337.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40344 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40344 | HTTPS FTP |
-Validation report
Summary document | emd_40344_validation.pdf.gz | 1.1 MB | Display | EMDB validaton report |
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Full document | emd_40344_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | emd_40344_validation.xml.gz | 24.6 KB | Display | |
Data in CIF | emd_40344_validation.cif.gz | 32.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40344 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40344 | HTTPS FTP |
-Related structure data
Related structure data | 8scbMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_40344.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | unsharpened map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.825 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: sharpened map
File | emd_40344_additional_1.map | ||||||||||||
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Annotation | sharpened map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: deepEMhancer processed map
File | emd_40344_additional_2.map | ||||||||||||
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Annotation | deepEMhancer processed map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half2
File | emd_40344_half_map_1.map | ||||||||||||
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Annotation | half2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half1
File | emd_40344_half_map_2.map | ||||||||||||
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Annotation | half1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : terminating rabbit ribosome
+Supramolecule #1: terminating rabbit ribosome
+Macromolecule #1: Ribosomal protein L8
+Macromolecule #2: Ribosomal protein L3
+Macromolecule #3: 60S ribosomal protein L4
+Macromolecule #4: Ribosomal_L18_c domain-containing protein
+Macromolecule #5: 60S ribosomal protein L6
+Macromolecule #6: 60S ribosomal protein L7
+Macromolecule #7: 60S ribosomal protein L7a
+Macromolecule #8: 60S ribosomal protein L9
+Macromolecule #9: 60S ribosomal protein L10
+Macromolecule #10: 60S ribosomal protein L11
+Macromolecule #11: eL13
+Macromolecule #12: 60S ribosomal protein L14
+Macromolecule #13: Ribosomal protein L15
+Macromolecule #14: uL13
+Macromolecule #15: uL22
+Macromolecule #16: Ribosomal protein L18
+Macromolecule #17: Ribosomal protein L19
+Macromolecule #18: eL20
+Macromolecule #19: eL21
+Macromolecule #20: eL22
+Macromolecule #21: Ribosomal protein L23
+Macromolecule #22: 60S ribosomal protein L24
+Macromolecule #23: eL23
+Macromolecule #24: uL24
+Macromolecule #25: 60S ribosomal protein L27
+Macromolecule #26: 60S ribosomal protein L27a
+Macromolecule #27: 60S ribosomal protein L29
+Macromolecule #28: eL30
+Macromolecule #29: eL31
+Macromolecule #30: eL32
+Macromolecule #31: eL33
+Macromolecule #32: 60S ribosomal protein L34
+Macromolecule #33: eL35
+Macromolecule #34: 60S ribosomal protein L36
+Macromolecule #35: Ribosomal protein L37
+Macromolecule #36: 60S ribosomal protein L38
+Macromolecule #37: eL39
+Macromolecule #38: Ubiquitin A-52 residue ribosomal protein fusion product 1
+Macromolecule #39: eL41
+Macromolecule #40: eL42
+Macromolecule #41: eL43
+Macromolecule #42: eL28
+Macromolecule #43: 60S acidic ribosomal protein P0
+Macromolecule #44: 60S ribosomal protein L12
+Macromolecule #45: NC
+Macromolecule #52: uS2 (SA)
+Macromolecule #53: eS1
+Macromolecule #54: uS5
+Macromolecule #55: Ribosomal protein S3
+Macromolecule #56: eS4 (S4 X isoform)
+Macromolecule #57: uS7
+Macromolecule #58: eS6
+Macromolecule #59: eS7
+Macromolecule #60: eS8
+Macromolecule #61: uS4
+Macromolecule #62: S10_plectin domain-containing protein
+Macromolecule #63: uS17
+Macromolecule #64: eS12
+Macromolecule #65: uS15
+Macromolecule #66: uS11
+Macromolecule #67: uS19
+Macromolecule #68: uS9
+Macromolecule #69: eS17
+Macromolecule #70: uS13
+Macromolecule #71: eS19
+Macromolecule #72: uS10
+Macromolecule #73: eS21
+Macromolecule #74: uS8
+Macromolecule #75: uS12
+Macromolecule #76: 40S ribosomal protein S24
+Macromolecule #77: eS25
+Macromolecule #78: 40S ribosomal protein S26
+Macromolecule #79: eS27
+Macromolecule #80: eS28
+Macromolecule #81: uS14
+Macromolecule #82: eS30
+Macromolecule #83: eS31
+Macromolecule #84: Receptor for Activated C Kinase 1 (RACK1)
+Macromolecule #86: Eukaryotic peptide chain release factor subunit 1
+Macromolecule #87: ATP binding cassette subfamily E member 1
+Macromolecule #46: P_tRNA
+Macromolecule #47: E_tRNA
+Macromolecule #48: 28S_rRNA
+Macromolecule #49: 5S_rRNA
+Macromolecule #50: 5.8S_rRNA
+Macromolecule #51: 18S_rRNA
+Macromolecule #85: mRNA
+Macromolecule #88: MAGNESIUM ION
+Macromolecule #89: ZINC ION
+Macromolecule #90: (2S,4aS)-2-cyclobutyl-10-methyl-3-phenyl-2,10-dihydropyrimido[4,5...
+Macromolecule #91: IRON/SULFUR CLUSTER
+Macromolecule #92: water
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.8 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |