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Our findings elucidate the interactions within the ADAM17\u2013iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.<\/jats:p>","DOI":"10.1073\/pnas.2500732122","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T13:38:36Z","timestamp":1749821916000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Structural insights into the activation and inhibition of the ADAM17\u2013iRhom2 complex"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9741-5082","authenticated-orcid":false,"given":"Joseph J.","family":"Maciag","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conner E.","family":"Slone","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Alnajjar","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Guion","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2945-2580","authenticated-orcid":false,"given":"Igal","family":"Ifergan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-3137","authenticated-orcid":false,"given":"Carl P.","family":"Blobel","sequence":"additional","affiliation":[{"name":"Departments of Medicine and of Biochemistry, Cell and Molecular Biology, Weill Cornell Medicine","place":["New York"]},{"name":"Arthritis and Tissue Degeneration Program, Hospital for Special Surgery","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1258-6371","authenticated-orcid":false,"given":"Tom C. 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