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2-oxoglutarate (2-OG)-dependent oxygenases have diverse roles in human biology. The inhibition of several 2-OG oxygenases is being targeted for therapeutic intervention, including for cancer, anemia, and ischemic diseases. We report a small-molecule probe for 2-OG oxygenases that employs a hydroxyquinoline template coupled to a photoactivable crosslinking group and an affinity-purification tag. Following studies with recombinant proteins, the probe was shown to crosslink to 2-OG oxygenases in human crude cell extracts, including to proteins at endogenous levels. This approach is useful for inhibitor profiling, as demonstrated by crosslinking to the histone demethylase FBXL11 (KDM2A) in HEK293T nuclear extracts. The results also suggest that small-molecule probes may be suitable for substrate identification studies.

Original publication

DOI

10.1016/j.chembiol.2011.03.007

Type

Journal article

Journal

Chem Biol

Publication Date

27/05/2011

Volume

18

Pages

642 - 654

Keywords

Cell Line, Cross-Linking Reagents, Dioxygenases, Enzyme Inhibitors, F-Box Proteins, Humans, Hydroxyquinolines, Jumonji Domain-Containing Histone Demethylases, Oxidoreductases, N-Demethylating, Photochemical Processes, Protein Structure, Tertiary, Small Molecule Libraries, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization