A strategy for modulation of enzymes in the ubiquitin system.
Andreas Ernst,George V. Avvakumov,Jiefei Tong,Yihui Fan,Yanling Zhao,Philipp Alberts,Avinash Persaud,John R. Walker,Ana-Mirela Neculai,Dante Neculai,Andrew Vorobyov,Pankaj Garg,Linda G. Beatty,Pak-Kei Chan,Yu Chi Juang,Marie-Claude Landry,Christina Yeh,Christina Yeh,Elton Zeqiraj,Konstantina Karamboulas,Abdellah Allali-Hassani,Masoud Vedadi,Mike Tyers,Mike Tyers,Jason Moffat,Frank Sicheri,Frank Sicheri,Laurence Pelletier,Laurence Pelletier,Daniel Durocher,Daniel Durocher,Brian Raught,Daniela Rotin,Jianhua Yang,Michael Moran,Sirano Dhe-Paganon,Sirano Dhe-Paganon,Sachdev S. Sidhu +37 more
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TLDR
This work used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography to report a method to target the myriad enzymes that govern ubiquitination of protein substrates.Abstract:
The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.read more
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Journal Article
Methods in Enzymology.
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Journal ArticleDOI
Ubiquitin Ligases: Structure, Function, and Regulation
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TL;DR: Current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms are summarized.
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Ubiquitination in disease pathogenesis and treatment
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Sailfish enables alignment-free isoform quantification from RNA-seq reads using lightweight algorithms
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Drugging the undruggables: exploring the ubiquitin system for drug development.
XiaoDong Huang,Vishva M. Dixit +1 more
TL;DR: A review of therapeutic intervention nodes in the ubiquitin-proteasome system can be found in this article, where the authors highlight the most promising strategies to target the UPS.
References
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Journal ArticleDOI
Increased Expression of Thymidylate Synthetase (TS), Ubiquitin Specific Protease 10 (USP10) and Survivin is Associated with Poor Survival in Glioblastoma Multiforme (GBM)
Jessica M. Grunda,L. Burton Nabors,Cheryl A. Palmer,David C. Chhieng,Adam D. Steg,Tom Mikkelsen,Robert B. Diasio,Kui Zhang,David B. Allison,William E. Grizzle,Wenquan Wang,G. Yancey Gillespie,Martin R. Johnson +12 more
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