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As one of four related mammalian kinases that phosphorylate the mRNA translation machinery substrate eIF2\u03b1, it has a central role in sensing several disparate proteotoxic stresses and preventing subsequent rounds of protein production. In this review, we will examine the latest research on the structural and molecular basis of HRI inhibition and activation, examining both regulatory biological interactions with proteins and cofactors. What emerges is that despite almost 75\u00a0years since the first identification of HRI, we still know remarkably little about how this kinase functions and is regulated.<\/jats:p>","DOI":"10.1042\/bst20250541","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:32:26Z","timestamp":1778837546000},"page":"561-569","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structural insights into HRI kinase activity and inhibition"],"prefix":"10.1042","volume":"54","author":[{"given":"Min","family":"Cao","sequence":"first","affiliation":[{"name":"1MRC Protein Phosphorylation and Ubiquitination Unit, Faculty of Life Sciences, University of Dundee, Dundee, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1386-4719","authenticated-orcid":false,"given":"Glenn\u00a0R.","family":"Masson","sequence":"additional","affiliation":[{"name":"2Division of Cancer Research, Faculty of Heath, University of Dundee, Ninewells Hospital, Dundee, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"2026051505322409000_B1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/0092-8674(77)90330-0","article-title":"Phosphorylation of initiation factor eIF-2 and the control of reticulocyte protein synthesis","volume":"11","author":"Farrell","year":"1977","journal-title":"Cell"},{"key":"2026051505322409000_B2","doi-asserted-by":"publisher","first-page":"5076","DOI":"10.1073\/pnas.76.10.5076","article-title":"Protein synthesis in rabbit reticulocytes: mechanism of protein synthesis inhibition by heme-regulated inhibitor","volume":"76","author":"Das","year":"1979","journal-title":"Proc. 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