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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
The NEDD4-1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma
Xi Huang,Huiyao Gu,Enfan Zhang,Qingxiao Chen,Wen Cao,Haimeng Yan,Jing Chen,Li Yang,Ning Lv,Jingsong He,Qing Yi,Zhen Cai +11 more
TL;DR: The results suggest that high NEDD4‐1 levels may be a potential new therapeutic target in MM.
Journal ArticleDOI
Flexibility and Design: Conformational Heterogeneity along the Evolutionary Trajectory of a Redesigned Ubiquitin.
TL;DR: It is suggested that increasing flexibility may be a useful strategy to escape local minima during initial directed evolution and protein design steps when creating new functions.
Journal ArticleDOI
Genome-wide scan highlights the role of candidate genes on phenotypic plasticity for age at first calving in Nellore heifers.
Lúcio Flávio Macedo Mota,Fernando B. Lopes,Gerardo Alves Fernandes Júnior,Guilherme J. M. Rosa,Ana Fabrícia Braga Magalhães,Roberto Carvalheiro,Roberto Carvalheiro,Lucia Galvão de Albuquerque,Lucia Galvão de Albuquerque +8 more
TL;DR: Gene set enrichment analyses identified important biological functions related to growth, hormone levels affecting female fertility, physiological processes involved in female pregnancy, gamete generation, ovulation cycle, and age at puberty that support complex interactions between the gonadotropic axes and sexual precocity in Nellore heifers.
Journal ArticleDOI
The business of deubiquitination – location, location, location
Erin S. Coyne,Simon S. Wing +1 more
TL;DR: This commentary focuses on localization of the enzymes as a critical regulatory mechanism which when integrated with control of expression, substrate activation, allosteric regulation, and post-translational modifications results in precise spatial and temporal deubiquitination of proteins and therefore specific physiological functions.
Journal ArticleDOI
Site-specific inhibition of the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 selectively impairs SUMO chain formation
Svenja Wiechmann,Anne Gärtner,Andreas Kniss,Andreas Stengl,Christian Behrends,Vladimir V. Rogov,Manuel S. Rodriguez,Volker Dötsch,Stefan Müller,Andreas Ernst,Andreas Ernst +10 more
TL;DR: It is proposed that the availability of the new chain-selective SUMO inhibitors reported here will enable a thorough investigation of poly-SUMO-mediated cellular processes, such as DNA damage responses and cell cycle progression.
References
More filters
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.
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.