{"doi":"10.1126/sciimmunol.adp0707","title":"Orientation-dependent CD45 inhibition with viral and engineered ligands","abstract":"CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as \"beads on a string\" that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses.","journal":"Science Immunology","year":2024,"id":449464,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9637,"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":1268783,"name":"Liu Daisy Liu","orcid":"0009-0005-2939-6787","position":1,"is_corresponding":false},{"id":241703,"name":"Nathanael A. Caveney","orcid":"0000-0003-4828-3479","position":2,"is_corresponding":false},{"id":260360,"name":"Kevin M. Jude","orcid":"0000-0002-3675-5136","position":3,"is_corresponding":false},{"id":720917,"name":"Won‐Ju Kim","orcid":"0000-0002-1800-0485","position":4,"is_corresponding":false},{"id":271873,"name":"Takeya Masubuchi","orcid":"0000-0001-6822-3049","position":5,"is_corresponding":false},{"id":271880,"name":"Enfu Hui","orcid":"0000-0001-7876-2783","position":6,"is_corresponding":false},{"id":225335,"name":"Robbie G. Majzner","orcid":"0000-0001-6969-8011","position":7,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":8,"is_corresponding":false},{"id":284392,"name":"Marta T. Borowska","orcid":"0000-0002-8223-530X","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:02:16.291892Z","pmid":"39454026","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":[]}