Structure of the ribosomal oxygenase OGFOD1 provides insights into the regio- and stereoselectivity of prolyl hydroxylases

Shoichiro Horita, John S. Scotti, Cyrille Thinnes, Yousef S. Mottaghi-Taromsari, Armin Thalhammer, Wei Ge, Weishen Aik, Christoph Loenarz, Christopher J. Schofield*, Michael A. McDonough*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)639-652
Number of pages14
JournalStructure
Volume23
Issue number4
DOIs
Publication statusPublished - Apr 2015

Scopus Subject Areas

  • Structural Biology
  • Molecular Biology

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