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Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- USP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve 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 signalling pathways in health and disease.
- Subjects :
- Zinc finger
0303 health sciences
Proteases
Ubiquitin binding
biology
Chemistry
Allosteric regulation
Small molecule
Chemical library
Cell biology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Ubiquitin
biology.protein
030217 neurology & neurosurgery
Function (biology)
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....0280f14159d3977569da61220540a369