Structure of the ribosomal oxygenase OGFOD1 provides insights into the regio- and stereoselectivity of prolyl hydroxylases.
Abstract
peer reviewedPost-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 A 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 A 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- journal article
- http://purl.org/coar/resource_type/c_6501
- info:eu-repo/semantics/article
- peer reviewed
- Amino Acid Sequence
- Binding Sites
- Carrier Proteins/antagonists & inhibitors/chemistry/metabolism
- Humans
- Molecular Docking Simulation
- Molecular Sequence Data
- Nuclear Proteins/antagonists & inhibitors/chemistry/metabolism
- Prolyl-Hydroxylase Inhibitors/pharmacology
- Protein Binding
- Saccharomyces cerevisiae/enzymology
- Saccharomyces cerevisiae Proteins/antagonists & inhibitors/chemistry/metabolism
- Substrate Specificity
- Life sciences
- Biochemistry, biophysics & molecular biology
- Sciences du vivant
- Biochimie, biophysique & biologie moléculaire