Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain

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（泛素特异性蛋白酶5）分解非锚定泛素化链，以回收游离单泛素，并是具有锌指泛素结合域（ZnF-UBD）的12种泛素特异性蛋白酶之一。这一独特的结构模块与底物定位或催化活性的别构调节相关联，但其细胞功能尚不明确。本研究针对USP5的ZnF-UBD筛选了化学库，将晶体与蛋白复合物结合，并生成了初步的结构-活性关系，从而促进了更强效和更具选择性的化合物的开发。该研究为发现化学探针，以阐明USP5 ZnF-UBD在蛋白酶体降解及其他泛素化信号通路在健康与疾病中的功能提供了框架。