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- PDB-7toq: Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptid... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7toq | |||||||||||||||
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Title | Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein poly-PR | |||||||||||||||
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![]() | RIBOSOME / ribosomal binding peptide / ALS/FTD-associated dipeptide repeat protein | |||||||||||||||
Function / homology | ![]() ribosomal subunit / exit from mitosis / optic nerve development / retinal ganglion cell axon guidance / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / phagocytic cup / ribosomal small subunit export from nucleus / rough endoplasmic reticulum / translation regulator activity ...ribosomal subunit / exit from mitosis / optic nerve development / retinal ganglion cell axon guidance / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / phagocytic cup / ribosomal small subunit export from nucleus / rough endoplasmic reticulum / translation regulator activity / gastrulation / MDM2/MDM4 family protein binding / cytosolic ribosome / class I DNA-(apurinic or apyrimidinic site) endonuclease activity / DNA-(apurinic or apyrimidinic site) lyase / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / ribosomal large subunit biogenesis / positive regulation of apoptotic signaling pathway / maturation of SSU-rRNA / small-subunit processome / spindle / mRNA 5'-UTR binding / rRNA processing / rhythmic process / positive regulation of canonical Wnt signaling pathway / regulation of translation / large ribosomal subunit / ribosome binding / ribosomal small subunit biogenesis / ribosomal small subunit assembly / retina development in camera-type eye / small ribosomal subunit / 5S rRNA binding / ribosomal large subunit assembly / cytosolic small ribosomal subunit / large ribosomal subunit rRNA binding / small ribosomal subunit rRNA binding / perikaryon / cytosolic large ribosomal subunit / cytoplasmic translation / cell differentiation / tRNA binding / mitochondrial inner membrane / rRNA binding / ribosome / structural constituent of ribosome / translation / ribonucleoprotein complex / cell division / DNA repair / mRNA binding / apoptotic process / synapse / dendrite / negative regulation of apoptotic process / nucleolus / perinuclear region of cytoplasm / endoplasmic reticulum / Golgi apparatus / DNA binding / RNA binding / zinc ion binding / nucleus / membrane / cytosol / cytoplasm Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() ![]() ![]() | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||||||||
![]() | Loveland, A.B. / Svidritskiy, E. / Susorov, D. / Lee, S. / Park, A. / Zvornicanin, S. / Demo, G. / Gao, F.B. / Korostelev, A.A. | |||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Authors: Anna B Loveland / Egor Svidritskiy / Denis Susorov / Soojin Lee / Alexander Park / Sarah Zvornicanin / Gabriel Demo / Fen-Biao Gao / Andrei A Korostelev / ![]() ![]() Abstract: Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ...Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD. | |||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 4.7 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 26035MC ![]() 7tooC ![]() 7topC ![]() 7torC ![]() 7tosC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-RNA chain , 6 types, 6 molecules A18SA25SA58SA5SMRNAPTRN
#1: RNA chain | Mass: 548024.188 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#2: RNA chain | Mass: 1182428.000 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#3: RNA chain | Mass: 50143.648 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#4: RNA chain | Mass: 38691.914 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#82: RNA chain | Mass: 3097.885 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() ![]() |
#84: RNA chain | Mass: 24802.785 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
+Protein , 21 types, 21 molecules AL02AL07AL08AL13AL16AL18AL20AL22AL25AL29AL30AL38AL40AL42ARACAS00AS07AS16AS19AS21AS26
+60S ribosomal protein ... , 25 types, 25 molecules AL03AL04AL05AL06AL09AL11AL12AL14AL15AL17AL19AL21AL23AL26AL27AL28AL31AL32AL33AL34AL35AL36AL37AL43EL28
-Ribosomal protein ... , 3 types, 3 molecules AL10AL24AS05
#13: Protein | Mass: 24511.861 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#27: Protein | Mass: 7512.774 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#54: Protein | Mass: 21525.941 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Protein/peptide , 4 types, 4 molecules AL39AL41ALP0PR
#42: Protein/peptide | Mass: 6295.562 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#44: Protein/peptide | Mass: 3213.075 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#47: Protein/peptide | Mass: 3298.991 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#83: Protein/peptide | Mass: 5104.186 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() |
+40S ribosomal protein ... , 25 types, 25 molecules AS01AS02AS03AS04AS06AS08AS09AS10AS11AS12AS13AS14AS15AS17AS18AS20AS22AS23AS24AS25AS27AS28AS29AS30AS31
-Non-polymers , 1 types, 4 molecules 
#85: Chemical | ChemComp-ZN / |
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-Details
Has ligand of interest | N |
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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: Mamalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein PR20 Type: RIBOSOME / Entity ID: #1-#84 / Source: MULTIPLE SOURCES | ||||||||||||||||||||
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Molecular weight | Value: 4 MDa / Experimental value: NO | ||||||||||||||||||||
Source (natural) |
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Buffer solution | pH: 7 | ||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Humidity: 95 % |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 30 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
EM software | Name: FREALIGN / Version: 9.11 / Category: 3D reconstruction |
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CTF correction | Type: PHASE FLIPPING ONLY |
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 63475 / Symmetry type: POINT |