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- PDB-7azy: Context-specific inhibition of eukaryotic translation by macrolid... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7azy | ||||||
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Title | Context-specific inhibition of eukaryotic translation by macrolide antibiotics | ||||||
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![]() | RIBOSOME / context-specific inhibition / macrolide antibiotic / telithromycin | ||||||
Function / homology | ![]() cleavage in ITS2 between 5.8S rRNA and LSU-rRNA of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / response to cycloheximide / SRP-dependent cotranslational protein targeting to membrane / GTP hydrolysis and joining of the 60S ribosomal subunit / Formation of a pool of free 40S subunits / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / L13a-mediated translational silencing of Ceruloplasmin expression / preribosome, large subunit precursor / ribosomal large subunit export from nucleus ...cleavage in ITS2 between 5.8S rRNA and LSU-rRNA of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / response to cycloheximide / SRP-dependent cotranslational protein targeting to membrane / GTP hydrolysis and joining of the 60S ribosomal subunit / Formation of a pool of free 40S subunits / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / L13a-mediated translational silencing of Ceruloplasmin expression / preribosome, large subunit precursor / ribosomal large subunit export from nucleus / protein-RNA complex assembly / regulation of translational fidelity / translational termination / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / maturation of LSU-rRNA / ribosomal large subunit biogenesis / macroautophagy / maintenance of translational fidelity / ribosomal large subunit assembly / modification-dependent protein catabolic process / rRNA processing / protein tag activity / ribosome biogenesis / 5S rRNA binding / large ribosomal subunit rRNA binding / cytosolic large ribosomal subunit / cytoplasmic translation / rRNA binding / negative regulation of translation / ribosome / protein ubiquitination / structural constituent of ribosome / translation / response to antibiotic / mRNA binding / ubiquitin protein ligase binding / RNA binding / nucleus / metal ion binding / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.877 Å | ||||||
![]() | Koller, T.O. / Wilson, D.N. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Context-specific action of macrolide antibiotics on the eukaryotic ribosome. Authors: Maxim S Svetlov / Timm O Koller / Sezen Meydan / Vaishnavi Shankar / Dorota Klepacki / Norbert Polacek / Nicholas R Guydosh / Nora Vázquez-Laslop / Daniel N Wilson / Alexander S Mankin / ![]() ![]() ![]() Abstract: Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of ...Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Cryo-EM structural analysis showed that the macrolide telithromycin binds in the tunnel of the engineered eukaryotic ribosome. Genome-wide analysis of cellular translation and biochemical studies demonstrated that the drug inhibits eukaryotic translation by preferentially stalling ribosomes at distinct sequence motifs. Context-specific action markedly depends on the macrolide structure. Eliminating macrolide-arrest motifs from a protein renders its translation macrolide-tolerant. Our data illuminate the prospects of adapting macrolides for protein-selective translation inhibition in eukaryotic cells. | ||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 4.3 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.5 MB | Display | ![]() |
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Full document | ![]() | 1.6 MB | Display | |
Data in XML | ![]() | 196.2 KB | Display | |
Data in CIF | ![]() | 344.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 11951MC 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 ... , 38 types, 38 molecules bcdefghIjkqMNOQRSUVWxylmnoprst...
-Protein , 1 types, 1 molecules P
#15: Protein | Mass: 14583.077 Da / Num. of mol.: 1 / Source method: isolated from a natural source Source: (natural) ![]() ![]() Strain: ATCC 204508 / S288c / References: UniProt: P0CH08 |
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-RNA chain , 3 types, 3 molecules EFG
#39: RNA chain | Mass: 1097477.875 Da / Num. of mol.: 1 / Source method: isolated from a natural source Source: (natural) ![]() ![]() Strain: ATCC 204508 / S288c |
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#40: RNA chain | Mass: 38951.105 Da / Num. of mol.: 1 / Source method: isolated from a natural source Source: (natural) ![]() ![]() Strain: ATCC 204508 / S288c / References: GenBank: 1329886537 |
#41: RNA chain | Mass: 50682.922 Da / Num. of mol.: 1 / Source method: isolated from a natural source Source: (natural) ![]() ![]() Strain: ATCC 204508 / S288c / References: GenBank: 1331532632 |
-Non-polymers , 2 types, 4 molecules ![](data/chem/img/TEL.gif)
![](data/chem/img/HOH.gif)
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#43: Chemical | ChemComp-TEL / |
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#44: Water | ChemComp-HOH / |
-Details
Has ligand of interest | Y |
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-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: 60S ribosomal subunit with 25S rRNA mutation G2400A and telithromycin bound in the nascent peptide exit tunnel Type: RIBOSOME / Entity ID: #1-#42 / Source: NATURAL | ||||||||||||||||||||||||||||||
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) | Organism: ![]() ![]() | ||||||||||||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: 5 Optical density at 260 nm. Approximatly 100 pmol of ribosome complex per grid. | ||||||||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid type: Quantifoil R3/3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK III / 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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Cs: 2.7 mm |
Image recording | Electron dose: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4371 |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 329333 | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.877 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 153893 / Num. of class averages: 3 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT | ||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6Q8Y Accession code: 6Q8Y / Source name: PDB / Type: experimental model |