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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.
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.
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.
CRISPR-Cas9 based target validation revealed that the sensitivity of the p53-reactivating compound RITA is independent of functional p53 and is reliant on the regulation of the DNA damage-activated Fanconi anemia pathway.
Negatively charged lipids act as allosteric modulators for structural changes and activation of the GPCR β2-adrenergic receptor through direct intracellular interactions between lipid headgroups and the receptor.
Stable-isotope tracing and metabolomics analysis comparing pre-adipocytes and differentiated adipocytes revealed a shift from glucose and glutamine utilization to increased branched chain amino acid catabolic flux to generate acetyl–coenzyme A.
The biosynthesis of iridoids, a class of bicyclic monoterpenes, features an atypical cyclization reaction catalyzed by iridoid synthase (ISY). Crystallographic and biochemical characterization of ISY from Catharanthus roseus provides insights into the ISY enzymatic mechanism and highlights similarities with the homologous progesterone 5β-reductase.
Characterization of the first class D β-lactamases in Gram-positive bacteria, including the Bacillaceae family, shows that one, BPU-1, is capable of hydrolyzing a wide variety of β-lactam antibiotics and has a unique substrate-binding mode.
Structure and functional characterization of BpHep, a heparanase from the invasive pathogenic bacterium Burkholderia pseudomallei, defines its glycosaminoglycan recognition mechanism and its catalytic mechanism as an endo-acting glycoside hydrolase.
A crystal structure of an RNA folding intermediate of the group II intron reveals a compact conformation that is stabilized by the sequential docking of downstream intron domains, providing new insights into RNA tertiary structure assembly.
Chemoproteomic studies have revealed that a Wnt-pathway inhibitor, CCT251545, is a potent and selective small-molecule chemical probe that inhibits the Mediator complex–associated protein kinases CDK8 and CDK19 through a type 1 binding mode and modulates the growth of Wnt-dependent tumors.
