{"doi":"10.1101/2024.10.07.617049","title":"SINE compounds activate exportin-1 degradation via an allosteric mechanism","abstract":"The nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes 1,2 . Selinexor, a covalent XPO1 inhibitor, and other Selective Inhibitor of Nuclear Export (SINEs) restore proper nuclear localization by blocking XPO1-cargo binding 2-7 . SINEs also induce XPO1 degradation via the Cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB8 7 . Here we elucidate the mechanism underlying the high-affinity engagement of CRL5 ASB8 with SINE-conjugated XPO1. Cryogenic electron microscopy (cryoEM) structures reveal that ASB8 binds to a cryptic site on XPO1, which becomes accessible only upon SINE conjugation. While molecular glue degraders typically interact with both CRL and the substrate 8-10 , SINEs bind to XPO1 without requiring interaction with ASB8 for efficient XPO1 degradation. Instead, an allosteric mechanism facilitates high affinity XPO1-ASB8 interaction, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also observed upon treatment of the endogenous itaconate derivate 4-octyl itaconate, which suggests a native mechanism that is inadvertently exploited by synthesized XPO1 inhibitors. This allosteric XPO1 degradation mechanism of SINE compounds expands the known modes of targeted protein degradation beyond the well-characterized molecular glue degraders and proteolysis targeting chimeras of CRL4.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486404,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":841402,"name":"Ho Yee Joyce Fung","orcid":"0000-0002-0502-1957","position":1,"is_corresponding":false},{"id":1330190,"name":"Bert Kwanten","orcid":"0000-0003-4459-5299","position":2,"is_corresponding":false},{"id":677089,"name":"Tolga Çağatay","orcid":"0000-0003-0256-7636","position":3,"is_corresponding":false},{"id":677091,"name":"Ashley B. Niesman","orcid":"0009-0008-0118-7483","position":4,"is_corresponding":false},{"id":347576,"name":"Maarten Jacquemyn","orcid":"0000-0003-2626-4189","position":5,"is_corresponding":false},{"id":648477,"name":"Mehdi Gharghabi","orcid":"0000-0001-8030-3121","position":6,"is_corresponding":false},{"id":1330191,"name":"Brecht Permentier","orcid":"0009-0000-5353-0919","position":7,"is_corresponding":false},{"id":777766,"name":"Binita Shakya","orcid":null,"position":8,"is_corresponding":false},{"id":1330626,"name":"Rhituparna Nandi","orcid":null,"position":9,"is_corresponding":false},{"id":369682,"name":"Joseph M. Ready","orcid":"0000-0003-1305-9581","position":10,"is_corresponding":false},{"id":309951,"name":"Trinayan Kashyap","orcid":null,"position":11,"is_corresponding":false},{"id":309955,"name":"Sharon Shacham","orcid":null,"position":12,"is_corresponding":false},{"id":308468,"name":"Yosef Landesman","orcid":"0000-0001-5542-5098","position":13,"is_corresponding":false},{"id":317880,"name":"Rosa Lapalombella","orcid":"0000-0001-6916-9400","position":14,"is_corresponding":false},{"id":347577,"name":"Dirk Daelemans","orcid":"0000-0001-7092-1153","position":15,"is_corresponding":false},{"id":345462,"name":"Yuh Min Chook","orcid":"0000-0002-4974-0726","position":16,"is_corresponding":false},{"id":841401,"name":"Casey E. Wing","orcid":"0000-0002-6437-0129","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:01.404471Z","pmid":"39416201","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":[]}