{"doi":"10.1101/2020.08.30.274597","title":"Ribosome inhibition by <i>C9ORF72</i> -ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM","abstract":"Abstract Toxic dipeptide repeat (DPR) proteins are produced from expanded G 4 C 2 hexanucleotide repeats in the C9ORF72 gene, which cause 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 cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124000,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":505501,"name":"E. Svidritskiy","orcid":null,"position":1,"is_corresponding":false},{"id":341659,"name":"Denis Susorov","orcid":"0009-0009-5925-9459","position":2,"is_corresponding":false},{"id":567718,"name":"Soojin Lee","orcid":"0000-0002-0383-5025","position":3,"is_corresponding":false},{"id":568193,"name":"Alexander Park","orcid":null,"position":4,"is_corresponding":false},{"id":504451,"name":"Gabriel Demo","orcid":"0000-0002-5472-9249","position":5,"is_corresponding":false},{"id":354156,"name":"Fen‐Biao Gao","orcid":"0000-0001-8873-5404","position":6,"is_corresponding":false},{"id":17838,"name":"Andrei A. Korostelev","orcid":"0000-0003-1588-717X","position":7,"is_corresponding":false},{"id":323179,"name":"A.B. Loveland","orcid":"0000-0001-9172-7747","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}