Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-inhibiting hypoxia-inducible factor.

Abstract

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.

• Authors: Ana Conejo-Garcia, Michael A McDonough, Christoph Loenarz, Luke A McNeill, Kirsty S Hewitson, Wei Ge, Benoît M Liénard, Christopher J Schofield, Ian J Clifton
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 20 Pg. 6125-8 (Oct 15 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20822901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Ketoglutaric Acids
• Repressor Proteins
• Mixed Function Oxygenases
• HIF1AN protein, human

Topics

• Binding Sites
• Catalytic Domain
• Humans
• Ketoglutaric Acids (chemistry, pharmacology)
• Mixed Function Oxygenases
• Models, Molecular
• Protein Binding
• Repressor Proteins (chemistry, metabolism)