{"doi":"10.1126/science.adk4422","title":"Continuous evolution of compact protein degradation tags regulated by selective molecular glues","abstract":"Conditional protein degradation tags (degrons) are usually >100 amino acids long or are triggered by small molecules with substantial off-target effects, thwarting their use as specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glue complexes (MG-PACE) and evolved a 36-amino acid zinc finger (ZF) degron (SD40) that binds the ubiquitin ligase substrate receptor cereblon in complex with PT-179, an orthogonal thalidomide derivative. Endogenous proteins tagged in-frame with SD40 using prime editing are degraded by otherwise inert PT-179. Cryo-electron microscopy structures of SD40 in complex with ligand-bound cereblon revealed mechanistic insights into the molecular basis of SD40's activity and specificity. Our efforts establish a system for continuous evolution of molecular glue complexes and provide ZF tags that overcome shortcomings associated with existing degrons.","journal":"Science","year":2024,"id":417178,"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":78,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"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":1202657,"name":"Stephan J. DeCarlo","orcid":"0000-0001-8054-2317","position":1,"is_corresponding":false},{"id":705291,"name":"Shourya S. Roy Burman","orcid":"0000-0001-9274-9104","position":2,"is_corresponding":false},{"id":349797,"name":"Vedagopuram Sreekanth","orcid":"0000-0002-7065-2675","position":3,"is_corresponding":false},{"id":225249,"name":"Andrew T. Nelson","orcid":"0000-0002-2591-0428","position":4,"is_corresponding":false},{"id":561748,"name":"Moritz Hunkeler","orcid":"0000-0003-0246-1188","position":5,"is_corresponding":false},{"id":1015047,"name":"Peter J. Chen","orcid":"0000-0002-1094-7180","position":6,"is_corresponding":false},{"id":299772,"name":"Katherine A. Donovan","orcid":"0000-0002-8539-5106","position":7,"is_corresponding":false},{"id":498129,"name":"Praveen Kokkonda","orcid":"0000-0002-2091-0242","position":8,"is_corresponding":false},{"id":806580,"name":"Praveen K. Tiwari","orcid":"0000-0002-8147-6312","position":9,"is_corresponding":false},{"id":411252,"name":"Veronika M. Shoba","orcid":"0000-0003-0402-7414","position":10,"is_corresponding":false},{"id":806579,"name":"Arghya Deb","orcid":"0000-0001-7607-3941","position":11,"is_corresponding":false},{"id":275621,"name":"Amit Choudhary","orcid":"0000-0002-8437-0150","position":12,"is_corresponding":false},{"id":262829,"name":"Eric S. Fischer","orcid":"0000-0001-7337-6306","position":13,"is_corresponding":false},{"id":32147,"name":"David R. Liu","orcid":"0000-0002-9943-7557","position":14,"is_corresponding":false},{"id":805680,"name":"Jaron A. M. Mercer","orcid":"0000-0001-7078-614X","position":0,"is_corresponding":true}],"reference_count":117,"raw_metadata":null,"created_at":"2026-07-19T01:56:50.743370Z","pmid":"38484051","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":[]}