期刊
NATURE CHEMICAL BIOLOGY
卷 10, 期 2, 页码 156-163出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1412
关键词
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资金
- National Center for Research Resources at the US National Institutes of Health (NIH) [RR-15301]
- US Department of Energy [ACO2-06CH11357]
- National Center for Research Resources [5P2ORR016464-11]
- National Institute of General Medical Sciences from the NIH [8 P20 GM103440-11]
- Canadian Institutes of Health Research [MOP-126129, MOP-57795]
- Ministere de renseignement superieur, de la recherche, de la science et de la technologie du Quebec through Genome Quebec
- Canadian Institutes of Health Research Postdoctoral Fellowship
- Canada Research Chair in structural biology
- Canada Research Chair in systems and synthetic biology
- MRC [MC_G0802522] Funding Source: UKRI
- Medical Research Council [MC_G0802522] Funding Source: researchfish
Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
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