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
A 2.2 Å resolution structure of the USP7 catalytic domain in a new space group elaborates upon structural rearrangements resulting from ubiquitin binding.
TL;DR: These structures support previous findings that the catalytic triad and switching loop are likely to be in unproductive conformations in the absence of ubiquitin and reveal previously unobserved electron density for blocking loop 1 (BL1) residues 410-419.
Journal ArticleDOI
Novel Insights Into E3 Ubiquitin Ligase in Cancer Chemoresistance.
TL;DR: The role of E3 ligase in cancer chemotherapy resistance and the underlying mechanism is explored and the growing number of E 3 ligases and their substrate proteins are summarized, which have emerged as crucial players in cancer chemoresistance and targeted therapies.
Journal ArticleDOI
A Structure-Based Strategy for Engineering Selective Ubiquitin Variant Inhibitors of Skp1-Cul1-F-Box Ubiquitin Ligases
Maryna Gorelik,Noah Manczyk,Noah Manczyk,Alevtina Pavlenco,Igor Kurinov,Sachdev S. Sidhu,Frank Sicheri,Frank Sicheri +7 more
TL;DR: The power of combining phage display with structure-based design to develop UbVs targeting specific protein surfaces is highlighted, and an optimized engineering strategy to generate specific binding UbVs against 17 additional Skp1-F-box complexes is employed.
Journal ArticleDOI
Fine-tuning the ubiquitin code at DNA double-strand breaks: deubiquitinating enzymes at work.
TL;DR: The current knowledge of how ub-mediated signaling at DSBs is controlled by DUBs is discussed, with main focus on Dubs targeting histone H2A and on their recent implication in stem cell biology and cancer.
Journal ArticleDOI
Optimal Effector Functions in Human Natural Killer Cells Rely upon Autocrine Bone Morphogenetic Protein Signaling
Neil C Robson,Laura Hidalgo,Tristan McAlpine,Heng Wei,Víctor G. Martínez,Ana Entrena,Gustavo J. Melen,Andrew S. MacDonald,Alexander T. Phythian-Adams,Rosa Sacedón,Eugene Maraskovsky,Jonathan Cebon,Manuel Ramírez,Angeles Vicente,Alberto Varas +14 more
TL;DR: Mechanistic investigations revealed that BMP signaling optimized IFNγ and global cytokine and chemokine production, phenotypic activation and proliferation, and autologous dendritic cell activation and target cytotoxicity, which identifies a novel auto-activatory pathway that is essential for optimal NK cell effector function.
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.