Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON M5G 1M1, Canada.
Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON M5G 1M1, Canada; Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
Cell Chem Biol. 2018 Aug 16;25(8):1017-1030.e9. doi: 10.1016/j.chembiol.2018.05.014. Epub 2018 Jun 28.
Acyldepsipeptides (ADEPs) are potential antibiotics that dysregulate the activity of the highly conserved tetradecameric bacterial ClpP protease, leading to bacterial cell death. Here, we identified ADEP analogs that are potent dysregulators of the human mitochondrial ClpP (HsClpP). These ADEPs interact tightly with HsClpP, causing the protease to non-specifically degrade model substrates. Dysregulation of HsClpP activity by ADEP was found to induce cytotoxic effects via activation of the intrinsic, caspase-dependent apoptosis. ADEP-HsClpP co-crystal structure was solved for one of the analogs revealing a highly complementary binding interface formed by two HsClpP neighboring subunits but, unexpectedly, with HsClpP in the compact conformation. Given that HsClpP is highly expressed in multiple cancers and has important roles in cell metastasis, our findings suggest a therapeutic potential for ADEPs in cancer treatment.
酰二肽（ADEPs）是一类有潜力的抗生素，它们可以使高度保守的十四聚体细菌 ClpP 蛋白酶的活性失调，导致细菌细胞死亡。在这里，我们鉴定出了 ADEP 的类似物，它们是人类线粒体 ClpP（HsClpP）的有效调节剂。这些 ADEPs 与 HsClpP 紧密结合，导致蛋白酶非特异性地降解模型底物。通过激活内在的、依赖半胱天冬酶的细胞凋亡，发现 ADEP 对 HsClpP 活性的失调会诱导细胞毒性作用。我们为其中一种类似物解析了 ADEP-HsClpP 共晶结构，揭示了由两个 HsClpP 相邻亚基形成的高度互补结合界面，但出人意料的是，HsClpP 处于紧凑构象。鉴于 HsClpP 在多种癌症中高度表达，并在细胞转移中具有重要作用，我们的研究结果表明 ADEPs 在癌症治疗中有治疗潜力。
