Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada.
Department of Pharmacology and Toxicology , University of Toronto , 1 King's College Circle , Toronto , Ontario M5S 1A8 , Canada.
J Med Chem. 2019 Nov 27;62(22):10144-10155. doi: 10.1021/acs.jmedchem.9b00988. Epub 2019 Nov 12.
USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signaling pathways in health and disease.
USP5 可将未锚定的多泛素链拆开，以回收游离的单泛素，是具有锌指泛素结合结构域（ZnF-UBD）的 12 种泛素特异性蛋白酶之一。该独特的结构模块与底物定位或催化活性的别构调节有关，但细胞功能尚不清楚。我们筛选了一个专注于 USP5 的 ZnF-UBD 的化学文库，将与蛋白质结合的命中化合物进行结晶，并生成了初步的结构-活性关系，这使得更有效和选择性的化合物得以开发。这项工作为发现化学探针以描绘 USP5 ZnF-UBD 在蛋白酶体降解以及健康和疾病中的其他泛素信号通路中的功能奠定了基础。
