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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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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Proteases in the Treatment of Cancer Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific
TL;DR: This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor–mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers.
OtherDOI
Targeting the Ubiquitination Cascade for Drug Discovery
TL;DR: In this article , the authors review advances in targeting ubiquitination for inhibitor development, focusing on the strategies, biological outcomes, and mode of action for E1/E2/E3 small-molecule inhibitors.
Deubiquitinating enzyme USP48 mediates pyroptosis and meliorates immune evasion in tumors by stabilizing GSDME expression
Journal ArticleDOI
Targeting Ras with protein engineering
Atílio Tomazini,Julia M. Shifman +1 more
TL;DR: In this paper , the first covalent small-molecule anti-Ras drug, sotorasib, was developed to inhibit the Ras G12C mutant, which is not a prevalent mutation in most cancer types.
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Next-generation sequencing of a combinatorial peptide phage library screened against ubiquitin identifies peptide aptamers that can inhibit the in vitro ubiquitin transfer cascade
Malgorzata Maria Lisowska,Fiona Rachael Lickiss,Maria Gil-Mir,Anne Huart,Zuzanna Trybala,Luke Way,Lenka Hernychová,Adam Krejci,Petr Muller,Radovan Krejcir,I. Zhukow,Przemyslaw Jurczak,Sylwia Rodziewicz-Motowidło,Kathryn L. Ball,Borivoj Vojtesek,Ted R. Hupp,Umesh Kalathiya +16 more
TL;DR: In this paper , the authors used next-generation deep sequencing platforms to identify peptide sequences isolated from phage-peptide libraries screened against Ubiquitin and its ortholog NEDD8.
References
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Book
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
Coot: model-building tools for molecular graphics.
Paul Emsley,Kevin Cowtan +1 more
TL;DR: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics.
Book
Molecular cloning : a laboratory manual
Joseph Sambrook,David W. Russell +1 more
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.
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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.