7too: Difference between revisions
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==Yeast 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein GR20== | |||
<StructureSection load='7too' size='340' side='right'caption='[[7too]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7too]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TOO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TOO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7too FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7too OCA], [https://pdbe.org/7too PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7too RCSB], [https://www.ebi.ac.uk/pdbsum/7too PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7too ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/RL19A_YEAST RL19A_YEAST] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Toxic dipeptide-repeat (DPR) proteins are produced from expanded G(4)C(2) 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. | |||
Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.,Loveland AB, Svidritskiy E, Susorov D, Lee S, Park A, Zvornicanin S, Demo G, Gao FB, Korostelev AA Nat Commun. 2022 May 19;13(1):2776. doi: 10.1038/s41467-022-30418-0. PMID:35589706<ref>PMID:35589706</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7too" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Ribosome 3D structures|Ribosome 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Saccharomyces cerevisiae]] | |||
[[Category: Demo G]] | |||
[[Category: Gao FB]] | |||
[[Category: Korostelev AA]] | |||
[[Category: Lee S]] | |||
[[Category: Loveland AB]] | |||
[[Category: Park A]] | |||
[[Category: Susorov D]] | |||
[[Category: Svidritskiy E]] | |||
[[Category: Zvornicanin S]] | |||
Latest revision as of 17:04, 6 November 2024
Yeast 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein GR20Yeast 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein GR20
Structural highlights
FunctionPublication Abstract from PubMedToxic dipeptide-repeat (DPR) proteins are produced from expanded G(4)C(2) 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. Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.,Loveland AB, Svidritskiy E, Susorov D, Lee S, Park A, Zvornicanin S, Demo G, Gao FB, Korostelev AA Nat Commun. 2022 May 19;13(1):2776. doi: 10.1038/s41467-022-30418-0. PMID:35589706[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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