ArticleThe Biochemical journal2025
Structural insights into allosteric inhibition of HRI kinase by heme binding via HDX-MS.
Article in The Biochemical journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Regulatory mechanism of heme-regulated inhibitor through autophosphorylation-driven activation and heme-induced deactivation.Journal of biochemistry · 2026Article
- FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.The EMBO journal · 2026Article
- Structural insights into HRI kinase activity and inhibition.Biochemical Society transactions · 2026Review
- Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.The Biochemical journal · 2026Review
- Article
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Authors and funding
5 authors.
Funding
Abstract
Heme-regulated inhibitor (HRI) is one of the four mammalian kinases that phosphorylate eIF2α, facilitating a cellular response to stress through the regulation of mRNA translation. Originally identified as a heme sensor in erythroid progenitor cells, HRI has since emerged as a potential therapeutic target in both cancer and neurodegeneration. Here, we characterise two modes of HRI inhibition using structural mass spectrometry, biochemistry, and biophysics. We examined several competitive ATP-mimetic inhibitors - dabrafenib, encorafenib, and GCN2iB - and compared them with the heme-mimetic allosteric inhibitor, hemin. By combining hydrogen-deuterium exchange mass spectrometry with protein models generated by AlphaFold 3, we investigated the structural basis of inhibition by dabrafenib and hemin. Our analysis revealed that hemin inhibition induces large-scale structural rearrangements in HRI, which are not observed with ATP-mimetic inhibitors. Our results suggest that HRI may be inhibited using two distinctly different modalities, which may guide future drug development.
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Registered trials
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