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We determined the cryo-EM structure of this complex and found that the E3\/49K protein is composed of three immunoglobulin domains assembled as \u201cbeads on a string\u201d 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.<\/jats:p>","DOI":"10.1126\/sciimmunol.adp0707","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T17:58:06Z","timestamp":1729879086000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["Orientation-dependent CD45 inhibition with viral and engineered ligands"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8223-530X","authenticated-orcid":true,"given":"Marta T.","family":"Borowska","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94063, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2939-6787","authenticated-orcid":true,"given":"Liu D.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94063, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4828-3479","authenticated-orcid":true,"given":"Nathanael A.","family":"Caveney","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94063, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3675-5136","authenticated-orcid":true,"given":"Kevin M.","family":"Jude","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94063, USA."},{"name":"Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94063, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won-Ju","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6822-3049","authenticated-orcid":true,"given":"Takeya","family":"Masubuchi","sequence":"additional","affiliation":[{"name":"Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-2783","authenticated-orcid":true,"given":"Enfu","family":"Hui","sequence":"additional","affiliation":[{"name":"Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6969-8011","authenticated-orcid":true,"given":"Robbie G.","family":"Majzner","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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