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A strategy for modulation of enzymes in the ubiquitin system.

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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.

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Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease

TL;DR: This work proposes that PLpro's higher affinity for K48-linked ubiquitin chains and ISG15 stems from a bivalent mechanism of binding, where two Ubiquitin-like domains prefer to bind in the palm domain of PLpro with the most distal ubiquitIn domain interacting with a “ridge” region of the thumb domain.
Journal ArticleDOI

Regulation of Proteolysis by Human Deubiquitinating Enzymes

TL;DR: The scope and regulation of the ubiquitin pathway is very similar to that of phosphorylation, with the DUBs serving the same functions as the phosphatase.
Journal ArticleDOI

Ubiquitination and the Regulation of Membrane Proteins.

TL;DR: The mechanisms and functions of ubiquitination of membrane proteins are summarized and specific examples of Ubiquitin-dependent regulation of membrane Protein Regulation are provided to downregulate the physiological outcomes.
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.

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

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

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.
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