Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
Cell Chem Biol. 2021 Jul 15;28(7):1000-1013. doi: 10.1016/j.chembiol.2021.04.002. Epub 2021 Apr 22.
Induced protein degradation accomplishes elimination, rather than inhibition, of pathological proteins. Key to the success of this novel therapeutic modality is the modification of proteins with ubiquitin chains, which is brought about by molecular glues or bivalent compounds that induce proximity between the target protein and an E3 ligase. The human genome encodes ∼600 E3 ligases that differ widely in their structures, catalytic mechanisms, modes of regulation, and physiological roles. While many of these enzymes hold great promise for drug discovery, few have been successfully engaged by small-molecule degraders. Here, we review E3 ligases that are being used for induced protein degradation. Based on these prior successes and our growing understanding of the biology and biochemistry of E3 ligases, we propose new ubiquitylation enzymes that can be harnessed for drug discovery to firmly establish induced protein degradation as a specific and efficient therapeutic approach.
诱导蛋白降解实现了病理性蛋白的消除，而非抑制。这种新型治疗模式的关键在于用泛素链修饰蛋白质，这是通过分子胶或双价化合物实现的，它们诱导靶蛋白与 E3 连接酶接近。人类基因组编码约 600 种 E3 连接酶，它们在结构、催化机制、调节方式和生理作用上差异很大。虽然这些酶中的许多都为药物发现带来了巨大的希望，但很少有被小分子降解剂成功利用。在这里，我们综述了用于诱导蛋白降解的 E3 连接酶。基于这些先前的成功以及我们对 E3 连接酶的生物学和生物化学的不断深入理解，我们提出了新的可用于药物发现的泛素化酶，以将诱导蛋白降解牢固确立为一种特异性和高效的治疗方法。
