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ORF45 was shown to be a kinase activator in cells but a kinase inhibitor in vitro, and its effects on the ERK-RSK complex are unknown. Here, we demonstrate that ORF45 binds ERK and RSK using optimized linear binding motifs. The crystal structure of the ORF45-ERK2 complex shows how kinase docking motifs recognize the activated form of ERK. The crystal structure of the ORF45-RSK2 complex reveals an AGC kinase docking system, for which we provide evidence that it is functional in the host. We find that ORF45 manipulates ERK-RSK signaling by favoring the formation of a complex, in which activated kinases are better protected from phosphatases and docking motif-independent RSK substrate phosphorylation is selectively up-regulated. As such, our data suggest that ORF45 interferes with the natural design of kinase docking systems in the host.<\/jats:p>","DOI":"10.1038\/s41467-022-28109-x","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T11:03:10Z","timestamp":1643108590000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5740-7835","authenticated-orcid":false,"given":"Anita","family":"Alexa","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8963-8163","authenticated-orcid":false,"given":"P\u00e9ter","family":"Sok","sequence":"additional","affiliation":[]},{"given":"Fridolin","family":"Gross","sequence":"additional","affiliation":[]},{"given":"Kriszti\u00e1n","family":"Albert","sequence":"additional","affiliation":[]},{"given":"Evan","family":"Kobori","sequence":"additional","affiliation":[]},{"given":"\u00c1d\u00e1m L.","family":"P\u00f3ti","sequence":"additional","affiliation":[]},{"given":"Gerg\u0151","family":"G\u00f3gl","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Bento","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4976-3311","authenticated-orcid":false,"given":"Ersheng","family":"Kuang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-6108","authenticated-orcid":false,"given":"Susan S.","family":"Taylor","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4189-7008","authenticated-orcid":false,"given":"Fanxiu","family":"Zhu","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Ciliberto","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8345-1311","authenticated-orcid":false,"given":"Attila","family":"Rem\u00e9nyi","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"28109_CR1","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1038\/2041104b0","volume":"204","author":"JJ Harvey","year":"1964","unstructured":"Harvey, J. 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