Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C

摘要: Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin ligase initiates metaphase-anaphase transition and mitotic exit by targeting proteins such as securin cyclin B1 for ubiquitin-dependent destruction proteasome. Because blocking an effective approach inducing tumour cell death, APC/C represents potential novel target cancer therapy. activation in mitosis requires binding of Cdc20 (ref. 5), which forms co-receptor with to recognize substrates containing box (D-box). Here we demonstrate can synergistically inhibit APC/C-dependent proteolysis simultaneously disrupting two protein-protein interactions within APC/C-Cdc20-substrate ternary complex. We identify small molecule, called apcin (APC inhibitor), binds competitively inhibits ubiquitylation D-box-containing substrates. Analysis crystal structure apcin-Cdc20 complex suggests occupies D-box-binding pocket on side face WD40-domain. The ability block amplified co-addition tosyl-l-arginine methyl ester, molecule blocks APC/C-Cdc20 interaction. This work simultaneous disruption multiple, weak inactivating machine.