Volume 12 Issue 1, January 2016

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.

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.

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.

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.

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.

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.

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.

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.

[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.