Beta-Actin Peptide-Based Inhibitors Of Histidine Methyltransferase Setd3

SETD3 was recently identified as the histidine methyltransferase responsible for N-3-methylation of His73 of beta-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected beta-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing beta-actin peptide was found to be the most potent SETD3 inhibitor (IC50=161 nM). Supporting our inhibition assays, a combination of computational docking and molecular dynamics simulations revealed that the His73 binding pocket for beta-actin in SETD3 is rigid and accommodates the inhibitor peptides with similar binding modes. Collectively, our work demonstrates that actin-based peptidomimetics can act as potent SETD3 inhibitors and provide a basis for further development of highly potent and selective inhibitors of SETD3.