A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants

摘要: RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three variants (UbVs), each binding selectively to or domain distinct ligase: monomeric UBE4B, phosphorylated active CBL, dimeric XIAP. Structural biochemical analyses revealed that UbVs specifically inhibited activity UBE4B CBL by blocking E2∼Ub site. Surprisingly, UbV selective for XIAP formed dimer stimulate stabilizing closed conformation. further verified inhibitory stimulatory functions cells. Our work provides general strategy inhibit activate RING/U-box resource research community modulate enzymes.