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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Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site
TL;DR: Cryo-Electron Microscopy is used to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323, to discover an unusual binding mode in which the inhibitor displaces part of the hydrophobic core of USp1.
Journal ArticleDOI
Proteomic profile of pre - B2 lymphoblasts from children with acute lymphoblastic leukemia (ALL) in relation with the translocation (12; 21)
Odile Costa,Pascale Schneider,Laurent Coquet,Philippe Chan,Dominique Penther,Elisabeth Legrand,Thierry Jouenne,Marc Vasse,Jean-Pierre Vannier +8 more
TL;DR: The lymphoblastes proteome in Childhood ALL is compared in accordance with the presence of t(12;21), indicator of good prognosis, usually, to identify marker candidates of leukemic aggressiveness and new t( 12;21) patients subgroups.
Journal ArticleDOI
Revisiting the phosphotyrosine binding pocket of Fyn SH2 domain led to the identification of novel SH2 superbinders.
Shuhao Li,Yang Zou,Dongping Zhao,Yuqing Yin,Jingyi Song,Ningning He,Huadong Liu,Dongmeng Qian,Lei Li,Haiming Huang +9 more
TL;DR: Three SH2 variants, named V3, V13 and V24, have comparable binding affinities with the previously identified SH2 triple‐mutant superbinder, and could be utilized as tools for the identification of pTyr‐containing proteins from tissues under different physiological or pathophysiological conditions.
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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.
Journal ArticleDOI
State of the art in (semi-)synthesis of Ubiquitin- and Ubiquitin-like tools
TL;DR: In this article , the progress in the chemical protein synthesis of state-of-the-art Ub and Ub-like chemical probes, their unique concepts and related discoveries in the ubiquitin field are discussed.
References
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