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Post-translational modifications (PTMs) of lysine side chains are important mediators of protein-protein interactions, particularly in chromatin. Photo-lysine, a diazirine analog of lysine, provides a tool to covalently capture proteins that bind lysine and its PTMs.
Cremeomycin is a diazo-containing natural product. Assignment of the functions of individual enzymes in the gene cluster for cremeomycin biosynthesis reveals a pathway by which Streptomyces cremeus converts L-aspartic acid into the nitrous acid needed for diazotization chemistry.
Cell-wall biogenesis in bacteria involves multiple intersecting gene networks. A powerful approach that allies synthetic lethality with small-molecule discovery has now been used to probe these networks and has revealed that the pathway for D-alanylation of teichoic acids in Staphylococcus aureus is a viable target for new antibacterials.
Two new studies describe potent and selective inhibitors of CDK8/CDK19. Application of these high-quality probes to several cancer models provides new mechanistic insight and reveals functional dichotomy with respect to Mediator kinases in signal-dependent gene regulation, with important implications for targeted cancer therapy.
Natural (βα)8-barrel proteins support diverse catalytic functions and are fertile scaffolds for engineering synthetic enzymes. The atomic-resolution structure determination of a computationally guided, de novo–designed symmetric barrel is a long-awaited advance that opens up new opportunities for enzyme design.
Phenotypic screening in cancer cell lines combined with chemogenomics analysis reveals a correlation between DNMDP sensitivity and increased PDE3A expression. DNMDP binding to PDE3A induces a switch resulting in interactions with SLFN12 and SIRT7.
A computational tool provides a systematic approach to determine the mechanisms of action of small molecules by examining correlations between basal gene expression and small-molecule sensitivity in cancer cell lines.
Applying an in vivo bacterial-based system for monitoring the influence of small molecules on the aggregation of model amyloid proteins expressed in the periplasm identified dopamine as a new inhibitor of hIAPP aggregation, a protein involved in type 2 diabetes mellitus.
Cyclophilin A binds a proline motif in human CrkII, preventing phosphorylation by Abl and EGFR. Decreased CrkII phosphorylation ensures interactions with the focal adhesion proteins paxillin and p130CAS to stimulate cellular migration.
Recently developed advanced microfluidics-based systems have outperformed known screening tools with respect to throughput, flexibility, sensitivity and tricks for hit recovery. This has enabled the discovery of novel and improved proteins from random mutagenesis libraries or metagenome-based sources.
A new technology platform called μSCALE combines the use of a microcapillary array with laser-based extraction to enable high-throughput biochemical and biophysical analysis and isolation of protein variants for protein-engineering applications.
The binding of small-molecule inhibitors of the RSV F glycoprotein in a central cavity in the prefusion conformation stabilizes this conformation and blocks the conformational changes required for fusion with host membranes.
Synthetic biology has expanded the availability of engineered bacterial systems for diverse applications and is now developing safeguards for their effective and secure use. The report of two synthetic gene circuit ‘kill switches’ provides new biocontainment mechanisms for engineered Escherichia coli.
[NiFe] hydrogenases contain a conserved arginine (R509) that is suspended over the Ni and Fe atoms. Biochemical, crystallographic and electrochemical analysis of an R509K mutant reveal >100-fold lower oxidation activity despite the maintenance of structural integrity.
A series of synthetic lethal strategies identifies a small-molecule inhibitor of Staphylococcus aureus DltB, links teichoic acid D-alanylation to virulence and identifies synergistic antibiotic drug combinations.
Despite substantial effort, the de novo design of a stable TIM-barrel protein fold has remained elusive. A Rosetta-based computational strategy identifies a unique 184-residue sequence that adopts a TIM-barrel structure, as revealed by X-ray crystallography.
