{"doi":"10.1126/sciadv.adf0797","title":"Structural insights into TRAP association with ribosome-Sec61 complex and translocon inhibition by a CADA derivative","abstract":"<jats:p>\n                    During cotranslational translocation, the signal peptide of a nascent chain binds Sec61 translocon to initiate protein transport through the endoplasmic reticulum (ER) membrane. Our cryo–electron microscopy structure of ribosome-Sec61 shows binding of an ordered heterotetrameric translocon-associated protein (TRAP) complex, in which TRAP-γ is anchored at two adjacent positions of 28\n                    <jats:italic>S</jats:italic>\n                    ribosomal RNA and interacts with ribosomal protein L38 and Sec61α/γ. Four transmembrane helices (TMHs) of TRAP-γ cluster with one C-terminal helix of each α, β, and δ subunits. The seven TMH bundle helps position a crescent-shaped trimeric TRAP-α/β/δ core in the ER lumen, facing the Sec61 channel. Further, our in vitro assay establishes the cyclotriazadisulfonamide derivative CK147 as a translocon inhibitor. A structure of ribosome-Sec61-CK147 reveals CK147 binding the channel and interacting with the plug helix from the lumenal side. The CK147 resistance mutations surround the inhibitor. These structures help in understanding the TRAP functions and provide a new Sec61 site for designing translocon inhibitors.\n                  </jats:p>","journal":"Science Advances","year":2023,"id":674493,"datarank":0.5456379239589579,"base_score":3.6375861597263857,"endowment":3.6375861597263857,"self_citation_contribution":0.5456379239589579,"citation_network_contribution":0.0,"self_endowment_contribution":0.5456379239589579,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1762276,"name":"Neesha R. Shewakramani","orcid":"0000-0002-4577-3491","position":1,"is_corresponding":false},{"id":364374,"name":"Brent De Wijngaert","orcid":"0000-0002-7551-8897","position":2,"is_corresponding":false},{"id":931622,"name":"Anita Camps","orcid":null,"position":3,"is_corresponding":false},{"id":931621,"name":"Becky Provinciael","orcid":null,"position":4,"is_corresponding":false},{"id":931140,"name":"Joren Stroobants","orcid":"0000-0002-1101-1034","position":5,"is_corresponding":false},{"id":1762277,"name":"Kai-Uwe Kalies","orcid":"0000-0001-8839-2376","position":6,"is_corresponding":false},{"id":1700138,"name":"Enno Hartmann","orcid":null,"position":7,"is_corresponding":false},{"id":841615,"name":"Piet Maes","orcid":"0000-0002-4571-5232","position":8,"is_corresponding":false},{"id":421728,"name":"Kurt Vermeire","orcid":"0000-0003-1123-1907","position":9,"is_corresponding":false},{"id":364382,"name":"Kalyan Das","orcid":"0000-0002-8897-324X","position":10,"is_corresponding":false},{"id":1762275,"name":"Eva Pauwels","orcid":"0000-0002-2794-0647","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Structural insights into TRAP association with ribosome-Sec61 complex and translocon inhibition by a CADA derivative","abstract":"<jats:p>\n                    During cotranslational translocation, the signal peptide of a nascent chain binds Sec61 translocon to initiate protein transport through the endoplasmic reticulum (ER) membrane. Our cryo–electron microscopy structure of ribosome-Sec61 shows binding of an ordered heterotetrameric translocon-associated protein (TRAP) complex, in which TRAP-γ is anchored at two adjacent positions of 28\n                    <jats:italic>S</jats:italic>\n                    ribosomal RNA and interacts with ribosomal protein L38 and Sec61α/γ. Four transmembrane helices (TMHs) of TRAP-γ cluster with one C-terminal helix of each α, β, and δ subunits. The seven TMH bundle helps position a crescent-shaped trimeric TRAP-α/β/δ core in the ER lumen, facing the Sec61 channel. Further, our in vitro assay establishes the cyclotriazadisulfonamide derivative CK147 as a translocon inhibitor. A structure of ribosome-Sec61-CK147 reveals CK147 binding the channel and interacting with the plug helix from the lumenal side. The CK147 resistance mutations surround the inhibitor. These structures help in understanding the TRAP functions and provide a new Sec61 site for designing translocon inhibitors.\n                  </jats:p>","is_dataset_classified":null,"base_score":3.6375861597263857,"endowment":3.6375861597263857,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36867692","pmcid":"PMC9984176","openalex_id":"https://openalex.org/W4323031742","authors":[],"funders":[],"total_grants":0,"fwci":3.2936,"citation_percentile":0.93477715,"influential_citations":0,"citation_trend":[{"year":2022,"count":1},{"year":2023,"count":8},{"year":2024,"count":8},{"year":2025,"count":16},{"year":2026,"count":4}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://www.science.org/doi/pdf/10.1126/sciadv.adf0797?download=true","host_type":"journal"},{"url":"https://www.science.org/doi/pdf/10.1126/sciadv.adf0797?download=true","host_type":"publisher"},{"url":"https://www.science.org/doi/pdf/10.1126/sciadv.adf0797","host_type":"publisher"},{"url":"https://doi.org/10.1126/sciadv.adf0797","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36867692","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9984176","host_type":"repository"},{"url":"https://lirias.kuleuven.be/handle/20.500.12942/715535","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9984176/pdf/sciadv.adf0797.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9984176","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9984176?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["RNA and protein synthesis mechanisms","RNA modifications and cancer","RNA Research and Splicing","SEC Translocation Channels","Cryoelectron Microscopy","Ribosomes","Calcium-Binding Proteins","Membrane Glycoproteins","Receptors, Peptide","Receptors, Cytoplasmic and Nuclear"],"mesh_terms":["SEC Translocation Channels","Calcium-Binding Proteins","Membrane Glycoproteins","Ribosomes","Receptors, Peptide","Receptors, Cytoplasmic and Nuclear","Cryoelectron Microscopy"],"keywords":["Translocon","Sec61","Ribosome","Endoplasmic reticulum","Biophysics","Cell biology","Crystallography","Membrane protein","Chemistry","Biology","Biochemistry","RNA","Membrane"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-16T17:03:42.779608Z","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":[]}