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Here we describe crystal structures of a viral OTU domain from the highly pathogenic Crimean\u2013Congo haemorrhagic fever virus (CCHFV) bound to Ub and to ISG15 at 2.5-\u212b and 2.3-\u212b resolution, respectively. The complexes provide a unique structural example of ISG15 bound to another protein and reveal the molecular mechanism of an ISG15 cross-reactive deubiquitinase. To accommodate structural differences between Ub and ISG15, the viral protease binds the \u03b2-grasp folds of Ub and C-terminal Ub-like domain of ISG15 in an orientation that is rotated nearly 75\u00b0 with respect to that observed for Ub bound to a representative eukaryotic OTU domain from yeast. Distinct structural determinants necessary for binding either substrate were identified and allowed the reengineering of the viral OTU protease into enzymes with increased substrate specificity, either for Ub or for ISG15. Our findings now provide the basis to determine in vivo the relative contributions of deubiquitination and deISGylation to viral immune evasion tactics, and a structural template of a promiscuous deubiquitinase from a haemorrhagic fever virus that can be targeted for inhibition using small-molecule-based strategies.<\/jats:p>","DOI":"10.1073\/pnas.1013388108","type":"journal-article","created":{"date-parts":[[2011,1,19]],"date-time":"2011-01-19T00:04:46Z","timestamp":1295395486000},"page":"2222-2227","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":103,"title":["Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease"],"prefix":"10.1073","volume":"108","author":[{"given":"Terrence W.","family":"James","sequence":"first","affiliation":[{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Frias-Staheli","sequence":"additional","affiliation":[{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John-Paul","family":"Bacik","sequence":"additional","affiliation":[{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesica M.","family":"Levingston Macleod","sequence":"additional","affiliation":[{"name":"Department of Microbiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazdak","family":"Khajehpour","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Garc\u00eda-Sastre","sequence":"additional","affiliation":[{"name":"Department of Microbiology,"},{"name":"Department of Medicine, Division of Infectious Diseases, and"},{"name":"Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Mark","sequence":"additional","affiliation":[{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,1,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nrm1700","article-title":"Ubiquitin and ubiquitin-like proteins as multifunctional signals","volume":"6","author":"Welchman RL","year":"2005","unstructured":"RL Welchman, C Gordon, RJ Mayer, Ubiquitin and ubiquitin-like proteins as multifunctional signals. 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