“X-Ray and Activity Fragment Screen Across Subfamilies of Lysine Demethylases”
Radoslaw Nowak, Department of Physics, Oxford University
Thanks to recent advances in automation, X-ray fragment screening is becoming increasingly popular method in rapidly identifying atomic resolution structures of protein-compound complexes. We combine X-ray based fragment screening with inhibition data for several subfamilies of human oxoglutarate dependent oxygenases to prioritize fragments for further lead development. We developed an X-ray fragment screening platform with JARID1B, JMJD1B, UTYC and JMJD2D and obtained crystal structures identified fragments occupying different parts of the active site pockets including putative allosteric sites, non-metal binding active sites and metal chelator sites. These starting points can be used to rationalize ligand binding hotspots for various subfamilies and accelerate development of selective chemical tools for this epigenetic enzyme family.