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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Patent
Viral polypeptide inhibitors
Marjolein Kikkert,Robert Cornells Martinus Knaap,Sachdev S. Sidhu,Wei Zhang,Brian Leonard Mark,Ben A. Bailey-Elkin +5 more
TL;DR: In this paper, the authors provide polypeptide inhibitors of viral proteins, useful in the treatment and prevention of viral infection, particularly for treating Middle East respiratory syndrome coronaviral (MERS-CoV) infection, Crimean-Congo hemorrhagic fever viral infection or the symptoms of infection.
Patent
Methods for identifying proteins and compounds that modulate the activity of otub1
TL;DR: In this paper, it was shown that OTUB1 cleavage of K48 polyubiquitin is stimulated by a select subset of E2 enzymes, and that this stimulation is regulated by the ubiquitin-charged state of the E2 and free UBCH5B.
Posted ContentDOI
What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks
TL;DR: In this article , the authors proposed that mutating residues regions exhibited highly correlated motions within the interaction network can efficiently optimize protein-protein interactions to create tight and selective protein binders, and validated their strategy using ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complexes.
Posted ContentDOI
Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14
Jason Shirian,Valeria Arkadash,Itay Cohen,Tamila Sapir,Evette S. Radisky,Niv Papo,Julia M. Shifman +6 more
TL;DR: This work engineered an inhibitor starting from a non-specific MMP inhibitor, N-TIMP2, that exhibited 1000-fold preference for M MP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions.
Journal ArticleDOI
Imaging of proteases using activity-based probes.
TL;DR: A critical review of the recent development of protease chemical probes can be found in this paper , which are small molecules that detect protease activity by interacting with protease active site, individual proteases as well as complex proteolytic networks.
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.
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.