Different modes of inhibitor binding to prolyl hydroxylase by combined use of X-ray crystallography and NMR spectroscopy of paramagnetic complexes.
In aqueous solution, azaquinolone inhibitors bind to prolyl 4-hydroxylase in two different orientations, as first detected by (19)F spectroscopy. This contrasts with the crystallographic structure where only one orientation has been determined. Dissection of the metal binding properties of the enzyme allowed structures of both complexes to be obtained in solution from (19)F and (13)C dipolar shifts in a labeled ligand.
Poppe
Leszek
L
Department of Molecular Structure, Amgen, Inc., Thousand Oaks, California 91320, USA. lpoppe@amgen.com
Tegley
Christopher M
CM
Li
Vivian
V
Lewis
Jeffrey
J
Zondlo
James
J
Yang
Evelyn
E
Kurzeja
Robert J M
RJ
Syed
Rashid
R
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D004791:Enzyme Inhibitors; D009287:Naphthyridines; D011393:Procollagen-Proline Dioxygenase