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

Mann MK, Franzoni I, de Freitas RF, Tempel W, Houliston S, Smith L, Vedadi M, Arrowsmith CH, Harding RJ, Schapira M
J Med Chem 62 10144-10155 (2019)
Related entries: 6dxh, 6dxt, 6p9g

Cited: 3 times
EuropePMC logo PMID: 31663737

Abstract

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.

Articles citing this publication (3)

  1. ProxyBind: A compendium of binding sites for proximity-induced pharmacology. Rovers E, Liu L, Schapira M. Comput Struct Biotechnol J 20 6163-6171 (2022)
  2. Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle. Mann MK, Wolf E, Silva M, Kwak HA, Wilson B, Bolotokova A, Wilson DJ, Harding RJ, Schapira M. ACS Omega 9 917-924 (2024)
  3. Zinc dynamics regulate early ovarian follicle development. Chen YY, Chen S, Ok K, Duncan FE, O'Halloran TV, Woodruff TK. J Biol Chem 299 102731 (2023)


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