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The model gastrointestinal nematode <jats:italic>Heligmosomoides polygyrus bakeri<\/jats:italic> secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.<\/jats:p>","DOI":"10.1038\/s41467-024-49550-0","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T03:40:33Z","timestamp":1718768433000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6842-6056","authenticated-orcid":false,"given":"Abhishek","family":"Jamwal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Colomb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1300-7407","authenticated-orcid":false,"given":"Henry J.","family":"McSorley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2870-1955","authenticated-orcid":false,"given":"Matthew K.","family":"Higgins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"49550_CR1","doi-asserted-by":"publisher","first-page":"101532","DOI":"10.1016\/j.smim.2021.101532","volume":"53","author":"HJ McSorley","year":"2021","unstructured":"McSorley, H. 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