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The cryo-electron microscopy (cryo-EM) structure of UL33 bound to the G\n                    <jats:sub>s<\/jats:sub>\n                    subtype of G protein reveals the N-terminal peptide as a tethered ligand reminiscent of the protease-activated receptors and adhesion GPCRs. This self-agonism induces a non-canonical active state that facilitates promiscuous G protein coupling, a plausible viral strategy for fine-tuning host signalling. Structure-guided mutagenesis disrupting key interactions between the N-terminus and its binding pocket abolishes G protein-mediated signalling, confirming the role of the N-terminus as a self-agonist. Our findings elucidate the structural basis for this activation mechanism and highlight the strategies employed by HCMV to hijack host G protein signalling.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-09660-5","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T06:55:32Z","timestamp":1770879332000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activation of cytomegalovirus-encoded G protein-coupled receptor UL33 by an innate N-terminal peptide"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6045-6320","authenticated-orcid":false,"given":"Anna K.","family":"Drzazga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6516-8424","authenticated-orcid":false,"given":"Shota","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0436-7124","authenticated-orcid":false,"given":"Caroline","family":"Wouters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2596-045X","authenticated-orcid":false,"given":"Felix","family":"Faas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouki","family":"Nishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Kamegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8070-1493","authenticated-orcid":false,"given":"Yoshinori","family":"Fujiyoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9600-3254","authenticated-orcid":false,"given":"Mette M.","family":"Rosenkilde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3617-7145","authenticated-orcid":false,"given":"Naotaka","family":"Tsutsumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"9660_CR1","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1038\/344774a0","volume":"344","author":"MS Chee","year":"1990","unstructured":"Chee, M. 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