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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Otubain 1: a non-canonical deubiquitinase with an emerging role in cancer.
TL;DR: Interestingly, in addition to catalytic DUB activity, OTUB1 displays a catalytic-independent, non-canonical activity where it inhibits the transfer of ubiquitin onto protein substrates by sequestration of E2 ubiquit in-conjugating enzymes.
Journal ArticleDOI
Vialinin A is a ubiquitin-specific peptidase inhibitor
Kiyoshi Okada,Yue Qi Ye,Kayoko Taniguchi,Ayaka Yoshida,Tomonori Akiyama,Yasukiyo Yoshioka,Jun-ichi Onose,Hiroyuki Koshino,Shunya Takahashi,Arata Yajima,Naoki Abe,Shunsuke Yajima +11 more
TL;DR: It is shown that ubiquitin-specific peptidase 5/isopeptidase T (USP5/IsoT) is a target molecule of vialinin A, identified by using a beads-probe method.
Journal ArticleDOI
Catching a DUB in the act: novel ubiquitin-based active site directed probes.
TL;DR: This work describes recent advances in the identification and characterization of the enzymes that remove ubiquitin, deubiquitylases (DUBs) and discusses future directions in reagent development for studying DUBs.
Journal ArticleDOI
Ubiquitin-Modifying Enzymes and Regulation of the Inflammasome.
TL;DR: Specific ubiquitin-modifying enzymes and ubiquitination events that orchestrate inflammatory responses are reviewed, with an emphasis on the NLRP3 inflammasome.
Journal ArticleDOI
Protein Engineering by Combined Computational and In Vitro Evolution Approaches
TL;DR: Two alternative strategies are commonly used to study protein-protein interactions (PPIs) and to engineer protein-based inhibitors and the combination of these approaches aids in the understanding of the specificity profiles of various PPIs.
References
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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.
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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.
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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.
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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.