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 ArticleDOI
Drugging the undruggable proteins in cancer: A systems biology approach
TL;DR: In this paper , the authors discuss integrative multiple omics approaches for understanding and modulating previously identified 'undruggable' targets such as members of the RAS family, MYC, TP53, and various E3 ligases and deubiquitinases.
Dissertation
Regulation of chromosome segregation and cohesion by the deubiquitinase USP37
TL;DR: This thesis presents an RNA interference screen for novel regulators of bipolar spindle assembly, which led to the finding that the deubiquitinase USP37 regulates chromosome segregation during mitosis.
Journal ArticleDOI
Probing Protein Interaction Networks by Combining MS-Based Proteomics and Structural Data Integration.
Guillaume Postic,Guillaume Postic,Julien Marcoux,Victor Reys,Jessica Andreani,Yves Vandenbrouck,Marie-Pierre Bousquet,Emmanuelle Mouton-Barbosa,Sarah Cianférani,Odile Burlet-Schiltz,Raphael Guerois,Gilles Labesse,Pierre Tufféry +12 more
TL;DR: A new bioinformatics protocol is introduced that integrates information of the multimeric protein 3D structures available in the Protein Data Bank using remote homology detection, as well as information related to Short Linear Motifs and interaction data from the BioGrid.
Journal ArticleDOI
Engineering ubiquitin to modulate the ubiquitin proteosome system
Andreas Ernst,Sachdev S. Sidhu +1 more
TL;DR: It has now been shown that ubiquitin itself can be used as a scaffold for generating inhibitors of USPs and other UPS enzymes, and may change this situation dramatically, at least at the research level.
Journal ArticleDOI
Chemical biology tools to study Deubiquitinases and Ubl proteases.
TL;DR: In this paper , the authors discuss how chemical biology has led to the development of activity-based probes and substrates that have been invaluable to the study of DUBs and ULPs.
References
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Molecular Cloning: A Laboratory Manual
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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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
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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
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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.