Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-inhibiting hypoxia-inducible factor.
Aromatic analogues of the 2-oxoglutarate co-substrate of the hypoxia-inducible factor hydroxylases are shown to bind at the active site iron: Pyridine-2,4-dicarboxylate binds as anticipated with a single molecule chelating the iron in a bidentate manner. The binding mode of a hydroxamic acid analogue, at least in the crystalline state, is unusual because two molecules of the inhibitor are observed at the active site and partial displacement of the iron binding aspartyl residue was observed.
Conejo-Garcia
Ana
A
The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
McDonough
Michael A
MA
Loenarz
Christoph
C
McNeill
Luke A
LA
Hewitson
Kirsty S
KS
Ge
Wei
W
Liénard
Benoît M
BM
Schofield
Christopher J
CJ
Clifton
Ian J
IJ
D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D007656:Ketoglutaric Acids / Q000737:chemistry* / Q000494:pharmacology*; D006899:Mixed Function Oxygenases; D008958:Models, Molecular; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*
D007656:Ketoglutaric Acids; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human