id="title" class="nomar"Chaperone-Enabled Studies of Epigenetic Regulation Enzymes
This biological project consists of investigators from the University of Chicago, University of Toronto, University of North Carolina, Johns Hopkins University, and Oxford University. They are partnered with the PSI High-Throughtput Structure Determination center NESG.
Marcin Paduch, target nominations, experiment design
The overarching goal of this project is to elucidate the molecular mechanism governing the catalysis and regulation of histone modification enzymes. We will use our Chaperone-Enabled Biology and Structure (CEBS) technology platform to study an important, but challenging group of epigenetic regulating enzymes. The lysine-specific histone methyltransferases (HMT) and their complementary partners, lysine demethylases (KDM) function as key mediators of epigenetic signaling through their actions as “writers and erasers” of post-translational modifications on histone proteins. Numerous recent studies have highlighted the importance of lysine methylation of histones leading to direct impact on DNA replication, repair, recombination, gene silencing, imprinting and RNA processes making these enzymes potential key targets for drug development. However, progress has been slow because they are multi-domain proteins that have been recalcitrant to structural and functional analyses. To overcome the existing barriers, we will generate specialized reagents called “synthetic affinity binders” or sABs that will be used as chaperones for crystallization, as well as customized affinity reagents for cell biological applications. To accomplish these goals we have assembled a team of protein engineers, structural biologists and cell biologists to exploit these reagents. We will also provide crystallization chaperones to the HPT Centers to increase probability of success of structure determination.
Structures, Targets, Publications and Technologies