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

DOI: 10.1016/j.str.2015.01.014
PMID: 25728928

Authors: Shoichiro Horita (University of Oxford) , John S Scotti (University of Oxford) , Cyrille Thinnes (University of Oxford) , Yousef S. Mottaghi-Taromsari (University of Oxford) , Armin Thalhammer (University of Oxford) , Wei Ge (University of Oxford) , Weishen Aik (University of Oxford) , Christoph Loenarz (University of Oxford) , Christopher J. Schofield (University of Oxford) , Michael A. Mcdonough (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 23 (4) , PAGES 639 - 652

State: Published (Approved)
Published: April 2015

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.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 23/11/2015 15:37

Documents:
PIIS0969212615000386.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)