{"doi":"10.1002/pro.70248","title":"An alternative pocket for binding the N‐degrons by the <scp>UBR1</scp> and <scp>UBR2</scp> ubiquitin <scp>E3</scp> ligases","abstract":"The UBR family of ubiquitin ligases binds to N-termini of their targets (known as N-degron) to induce their ubiquitination and degradation via a conserved domain known as UBR-box. UBR1 and UBR2 share the highest sequence homology among the family, and substantial structural studies were previously performed for substrate binding by the UBR-boxes of UBR1 and UBR2. Here, we describe a new pocket in the UBR-boxes of UBR1 and UBR2 for binding the second residues of N-degrons through determining five co-crystal structures of the UBR-boxes with various N-degron peptides. Together with binding affinities measured by fluorescence polarization, we show that the two highly homologous UBR-boxes can interact with the second residue of an N-degron differently. In addition, the UBR-boxes undergo different conformational changes when binding N-degrons. Furthermore, we demonstrate that the sidechain of the third amino acid of an N-degron has no contribution to binding the UBR-boxes. These findings represent a new conceptual advancement for the UBR E3 ligases and the new insights described here can be leveraged for developing their selective ligands for research and potential therapies.","journal":"Protein Science","year":2025,"id":545770,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":202029,"name":"D. Chen","orcid":null,"position":1,"is_corresponding":false},{"id":1249029,"name":"Tianchen Ren","orcid":"0009-0009-5241-4022","position":2,"is_corresponding":false},{"id":1142633,"name":"N. Thomas","orcid":null,"position":3,"is_corresponding":false},{"id":635994,"name":"Jian Wu","orcid":"0000-0002-8031-9462","position":4,"is_corresponding":false},{"id":249510,"name":"Banumathi Sankaran","orcid":"0000-0002-3266-8131","position":5,"is_corresponding":false},{"id":1437489,"name":"Renee Jones","orcid":null,"position":6,"is_corresponding":false},{"id":232971,"name":"Susan S. Taylor","orcid":"0000-0002-7702-6108","position":7,"is_corresponding":false},{"id":1058416,"name":"Yuan Chen","orcid":"0000-0002-1510-182X","position":8,"is_corresponding":false},{"id":1437026,"name":"Shih‐Ting Huang","orcid":"0000-0001-8261-7079","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":null,"created_at":"2026-07-19T02:53:27.751050Z","pmid":"40880185","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":[]}