Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.
Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Québec H3C 3J7, Canada.
Nat Chem Biol. 2014 Feb;10(2):156-163. doi: 10.1038/nchembio.1412. Epub 2013 Dec 15.
Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
泛素与泛素蛋白酶体系统（UPS）酶之间弱的蛋白相互作用介导泛素与底物的共价连接，这种弱相互作用有助于将泛素定位以实现最佳的催化转移。我们发现一种 E2 泛素缀合酶 Cdc34A 的小分子抑制剂 CC0651 通过捕获泛素与 E2 供体泛素结合位点之间的弱相互作用来发挥作用。三元复合物 CC0651-Cdc34A-泛素的结构揭示了抑制剂与由 Cdc34A 和泛素形成的复合结合口袋结合。CC0651 还抑制了 Cdc34A-泛素硫酯的自发水解速率，而不降低 Cdc34A 与 E3 酶的 RING 结构域亚基之间的相互作用。通过小分子稳定泛素与 UPS 酶之间的许多其他弱相互作用可能是一种可行的策略，可选择性抑制不同的 UPS 活性。
