- EMDB-40344: Terminating ribosome with SRI-41315 -
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Basic information
Entry
Database: EMDB / ID: EMD-40344
Title
Terminating ribosome with SRI-41315
Map data
unsharpened map
Sample
Complex: terminating rabbit ribosome
Protein or peptide: x 80 types
RNA: x 7 types
Ligand: x 5 types
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 / laminin receptor activity ...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 / laminin receptor activity / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / regulation of G1 to G0 transition / exit from mitosis / 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 / mammalian oogenesis stage / retinal ganglion cell axon guidance / G1 to G0 transition / activation-induced cell death of T cells / Protein hydroxylation / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / phagocytic cup / Eukaryotic Translation Termination / ribosomal small subunit binding / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / TOR signaling / T cell proliferation involved in immune response / protein-RNA complex assembly / ribosomal small subunit export from nucleus / negative regulation of ubiquitin-dependent protein catabolic process / erythrocyte development / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / translation regulator activity / cellular response to actinomycin D / ribosomal subunit export from nucleus / cytosolic ribosome / translational termination / laminin binding / rough endoplasmic reticulum / 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) / gastrulation / MDM2/MDM4 family protein binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / 90S preribosome / 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) / maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / maturation of LSU-rRNA / ribosomal large subunit biogenesis / cellular response to leukemia inhibitory factor / maturation of SSU-rRNA / positive regulation of translation / translational initiation / positive regulation of apoptotic signaling pathway / small-subunit processome / protein kinase C binding / positive regulation of protein-containing complex assembly / placenta development / cellular response to gamma radiation / mRNA 5'-UTR binding / transcription coactivator binding / Regulation of expression of SLITs and ROBOs / modification-dependent protein catabolic process / cytoplasmic ribonucleoprotein granule / spindle / G1/S transition of mitotic cell cycle / rRNA processing / protein tag activity / antimicrobial humoral immune response mediated by antimicrobial peptide / positive regulation of canonical Wnt signaling pathway / rhythmic process / ribosome biogenesis / ribosome binding / glucose homeostasis / retina development in camera-type eye / virus receptor activity / 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 / perikaryon / cytosolic small ribosomal subunit / defense response to Gram-negative bacterium / cell cycle / killing of cells of another organism / cytoplasmic translation / cytosolic large ribosomal subunit Similarity search - Function
: / RLI, domain 1 / RLI1 / RNase L inhibitor RLI-like, possible metal-binding domain / Possible Fer4-like domain in RNase L inhibitor, RLI / Peptide chain release factor eRF1/aRF1 / eRF1, domain 1 / eRF1 domain 2 / eRF1 domain 2 / eRF1 domain 1 ...: / RLI, domain 1 / RLI1 / RNase L inhibitor RLI-like, possible metal-binding domain / Possible Fer4-like domain in RNase L inhibitor, RLI / Peptide chain release factor eRF1/aRF1 / eRF1, domain 1 / eRF1 domain 2 / eRF1 domain 2 / eRF1 domain 1 / eRF1 domain 1/Pelota-like / eRF1 domain 3 / eRF1, domain 2 superfamily / eRF1 domain 3 / eRF1_1 / 4Fe-4S binding domain / 60s Acidic ribosomal protein / 60S acidic ribosomal protein P0 / 40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Ubiquitin-like protein FUBI / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / : / : / Ribosomal protein L30e / Ribosomal protein L2, archaeal-type / Ribosomal protein L28e / Ribosomal L15/L27a, N-terminal / Ribosomal protein L23 / 50S ribosomal protein L10, insertion domain superfamily / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / 60S ribosomal protein L10P, insertion domain / Insertion domain in 60S ribosomal protein L10P / : / Ribosomal protein S26e signature. / : / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein S26e / Ribosomal protein S26e superfamily / Ribosomal protein S26e / Ribosomal protein S21e, conserved site / Ribosomal protein S21e signature. / Ribosomal protein S12e signature. / metallochaperone-like domain / Ribosomal protein S12e / TRASH domain / Ribosomal protein S19e, conserved site / Ribosomal protein S19e signature. / Small (40S) ribosomal subunit Asc1/RACK1 / Ribosomal protein S2, eukaryotic / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein S21e / Ribosomal protein L29e / Ribosomal L29e protein family / S27a-like superfamily / 40S Ribosomal protein S10 / Ribosomal protein S10, eukaryotic/archaeal / Plectin/S10, N-terminal / Plectin/S10 domain / Ribosomal protein S25 / S25 ribosomal protein / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein S27a / : / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S17e, conserved site / Ribosomal protein S17e signature. / Ribosomal protein S8e subdomain, eukaryotes / Ribosomal protein S30 / Ribosomal protein S30 / 40S ribosomal protein S29/30S ribosomal protein S14 type Z / Ribosomal protein L27e, conserved site / Ribosomal protein L27e signature. / Ribosomal protein S7e signature. / Ribosomal protein L44e signature. / Ribosomal protein L10e, conserved site / Ribosomal protein L10e signature. / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein L10e / Ribosomal protein L19, eukaryotic / Ribosomal protein S19e / Ribosomal protein S3Ae, conserved site / Ribosomal protein S19e / Ribosomal protein S3Ae signature. / Ribosomal_S19e / Ribosomal protein S27e signature. / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein S4e signature. Similarity search - Domain/homology
Small ribosomal subunit protein eS32 / Ubiquitin-ribosomal protein eL40 fusion protein / Large ribosomal subunit protein uL16 / Small ribosomal subunit protein uS4 / Large ribosomal subunit protein eL24 / Large ribosomal subunit protein uL23 / Large ribosomal subunit protein eL33 / Small ribosomal subunit protein eS12 / ATP binding cassette subfamily E member 1 / Large ribosomal subunit protein eL29 ...Small ribosomal subunit protein eS32 / Ubiquitin-ribosomal protein eL40 fusion protein / Large ribosomal subunit protein uL16 / Small ribosomal subunit protein uS4 / Large ribosomal subunit protein eL24 / Large ribosomal subunit protein uL23 / Large ribosomal subunit protein eL33 / Small ribosomal subunit protein eS12 / ATP binding cassette subfamily E member 1 / Large ribosomal subunit protein eL29 / Small ribosomal subunit protein uS9 / Large ribosomal subunit protein eL31 / Large ribosomal subunit protein eL21 / Large ribosomal subunit protein uL29 / Small ribosomal subunit protein uS10 / Small ribosomal subunit protein RACK1 / Ubiquitin-ribosomal protein eS31 fusion protein / Large ribosomal subunit protein eL6 / Large ribosomal subunit protein uL11 / Large ribosomal subunit protein uL15 / Small ribosomal subunit protein uS15 / Large ribosomal subunit protein uL10 / Large ribosomal subunit protein uL24 / Small ribosomal subunit protein eS1 / Large ribosomal subunit protein eL8 / Small ribosomal subunit protein eS7 / Large ribosomal subunit protein uL4 / Large ribosomal subunit protein uL6 / Large ribosomal subunit protein eL43 / Large ribosomal subunit protein uL18 / Large ribosomal subunit protein eL14 / Small ribosomal subunit protein uS12 / Large ribosomal subunit protein eL15 / 40S ribosomal protein S24 / Large ribosomal subunit protein uL14 / Ubiquitin-like FUBI-ribosomal protein eS30 fusion protein / Small ribosomal subunit protein eS25 / Large ribosomal subunit protein eL30 / Large ribosomal subunit protein eL18 / Small ribosomal subunit protein eS26 / Small ribosomal subunit protein uS7 / Small ribosomal subunit protein uS8 / Small ribosomal subunit protein eS28 / Ribosomal protein L19 / Small ribosomal subunit protein eS8 / Small ribosomal subunit protein eS4 / Large ribosomal subunit protein uL3 / Small ribosomal subunit protein uS2 / Small ribosomal subunit protein eS6 / Small ribosomal subunit protein eS21 / Small ribosomal subunit protein eS19 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein uS13 / Small ribosomal subunit protein eS10 / Small ribosomal subunit protein uS17 / Large ribosomal subunit protein eL22 / Large ribosomal subunit protein uL2 / Large ribosomal subunit protein eL39 / Large ribosomal subunit protein eL36 / Small ribosomal subunit protein eS17 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL5 / Large ribosomal subunit protein uL22 / Large ribosomal subunit protein eL27 / Large ribosomal subunit protein eL34 / Small ribosomal subunit protein eS27 / Large ribosomal subunit protein eL38 / Small ribosomal subunit protein uS19 / Large ribosomal subunit protein eL42 / Large ribosomal subunit protein eL32 / Small ribosomal subunit protein uS11 / Large ribosomal subunit protein eL28 / Small ribosomal subunit protein uS14 / Eukaryotic peptide chain release factor subunit 1 / Large ribosomal subunit protein eL37 Similarity search - Component
Biological species
Oryctolagus cuniculus (rabbit) / Homo sapiens (human)
Method
single particle reconstruction / cryo EM / Resolution: 2.5 Å
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
DP2GM137415
United States
David and Lucile Packard Foundation
United States
American Heart Association
287375208
United States
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.
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