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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Patent
Probes and assays for measuring e3 ligase activity
TL;DR: In this article, it was shown that C-terminal ubiquitin thioesters can undergo a direct transthiolation reaction with the catalytic cysteine of the HECT E3 ligase RSP5 and form a catalytically active Rsp5-Ub thioester.
Journal ArticleDOI
The Multifaceted Role of the Ubiquitin Proteasome System in Pathogenesis and Diseases
Zane Stekel,Yi Sheng,Wei Zhang +2 more
TL;DR: In this Special Issue, seven original research and review articles are assembled to provide insights on the multifaceted role of the UPS in pathogenesis and disease, covering the areas of molecular and cellular mechanisms of UPS enzymes, biochemical and biophysical characterization strategies, drug development, and targeted protein degradation.
Dissertation
Computational Modeling of Protein Structure, Function, and Binding Hotspots
TL;DR: In this paper, the authors propose a method to solve the problem of the problem: this paper... ]].. [1] ]] ] ] ]] [2
Posted ContentDOI
SCFFBXW11 complex targets interleukin-17 receptor A for ubiquitin-proteasome-mediated degradation
TL;DR: In this article , the authors showed that IL-17RA was targeted by F-box and WD repeats domain containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation.
Journal ArticleDOI
A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
Wynton D. McClary,Alexis Catala,Wei Zhang,Fabia Gamboni,Monika Dzieciatkowska,Sachdev S. Sidhu,Angelo D'Alessandro,Carlos Enrique Catalano +7 more
TL;DR: It is demonstrated that the λ "designer nanoparticles" represent a powerful system for the intracellular delivery of biologics in a defined dose.
References
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Book
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TL;DR: Molecular Cloning has served as the foundation of technical expertise in labs worldwide for 30 years as mentioned in this paper and has been so popular, or so influential, that no other manual has been more widely used and influential.
Journal ArticleDOI
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Book
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TL;DR: The content has been entirely recast to include nucleic-acid based methods selected as the most widely used and valuable in molecular and cellular biology laboratories.
Journal ArticleDOI
Phaser crystallographic software
Airlie J. McCoy,Ralf W. Grosse-Kunstleve,Paul D. Adams,Martyn Winn,Laurent C. Storoni,Randy J. Read +5 more
TL;DR: A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
Journal ArticleDOI
Refinement of macromolecular structures by the maximum-likelihood method.
TL;DR: The likelihood function for macromolecular structures is extended to include prior phase information and experimental standard uncertainties and the results derived are consistently better than those obtained from least-squares refinement.