TY - JOUR
T1 - Structure of the ribosomal oxygenase OGFOD1 provides insights into the regio- and stereoselectivity of prolyl hydroxylases
AU - Horita, Shoichiro
AU - Scotti, John S.
AU - Thinnes, Cyrille
AU - Mottaghi-Taromsari, Yousef S.
AU - Thalhammer, Armin
AU - Ge, Wei
AU - Aik, Weishen
AU - Loenarz, Christoph
AU - Schofield, Christopher J.
AU - McDonough, Michael A.
N1 - Funding Information:
We thank the Japan Society for the Promotion of Science (S.H.), the Rhodes Trust (J.S.S.), the British Heart Foundation, the Wellcome Trust, and the Biotechnology and Biological Sciences Research Council for financial support; Ray Owens, Oxford Protein Production Facility, for contributing an OGFOD1 plasmid; the staff at Diamond Light Source; and P.J. Ratcliffe, M. Cockman, C.W. Pugh, and F.M. Ashcroft for discussions.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/4
Y1 - 2015/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930189427&partnerID=8YFLogxK
U2 - 10.1016/j.str.2015.01.014
DO - 10.1016/j.str.2015.01.014
M3 - Journal article
C2 - 25728928
AN - SCOPUS:84930189427
SN - 0969-2126
VL - 23
SP - 639
EP - 652
JO - Structure
JF - Structure
IS - 4
ER -