Post-translational ribosomal protein hydroxylation is catalyzed by 2-oxoglutarate (2OG) and ferrous iron dependent oxygenases, and occurs in prokaryotes and eukaryotes. OGFOD1 catalyzes trans-3 ...prolyl hydroxylation at Pro62 of the small ribosomal subunit protein uS12 (RPS23) and is conserved from yeasts to humans. We describe crystal structures of the human uS12 prolyl 3-hydroxylase (OGFOD1) and its homolog from Saccharomyces cerevisiae (Tpa1p): OGFOD1 in complex with the broad-spectrum 2OG oxygenase inhibitors; N-oxalylglycine (NOG) and pyridine-2,4-dicarboxylate (2,4-PDCA) to 2.1 and 2.6 Å resolution, respectively; and Tpa1p in complex with NOG, 2,4-PDCA, and 1-chloro-4-hydroxyisoquinoline-3-carbonylglycine (a more selective prolyl hydroxylase inhibitor) to 2.8, 1.9, and 1.9 Å resolution, respectively. Comparison of uS12 hydroxylase structures with those of other prolyl hydroxylases, including the human hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs), reveals differences between the prolyl 3- and prolyl 4-hydroxylase active sites, which can be exploited for developing selective inhibitors of the different subfamilies.
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•Crystal structures of human OGFOD1 in complex with inhibitors are presented•The OGFOD1 and PHDs likely share a common ancestor•The OGFOD1 active site is comparable with hypoxia-inducible factor prolyl hydroxylase•Differences between OGFOD1 and PHD2 can be exploited for inhibitor design
Horita et al. present structures of the first prolyl 3-hydroxylase from humans, OGFOD1, in complex with small-molecule inhibitors. The results shed light on the catalytic mechanisms and evolution of the OGFOD1 subfamily and the related “oxygen-sensing” hypoxia-inducible factor trans-P4Hs (PHDs).
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