News & Views in 2010

Protein structures are considerably stabilized by local interactions. A new computational and structural analysis discovers that n→π^* interactions between consecutive residues are stabilizing and ubiquitous in a variety of secondary structures.

The susceptibility of organisms to chemical perturbation differs as a result of defenses that limit the permeation of small molecules. Screening for permeation, rather than bioactivity, to identify a priori organism-specific chemical space offers an intriguing approach to phenotypic assays and potentially addresses some fundamental challenges in drug discovery.

Epistatic maps are used to delineate the modes of interaction of genes in various cellular pathways. A new epistatic map of nearly 400 genes involved in plasma membrane biology has revealed unexpected modes of regulation of endocytosis and sphingolipid metabolism.

The kinetics of the acylation, deacylation and reacylation cycle are important for localization and function of Ras as well as other key signaling proteins. A new small-molecule inhibitor may put the brakes on Ras by inhibiting the deacylation enzyme APT1.

Systems biology methods accumulate a vast array of information to generate hypotheses and discover new cellular relationships. A combination of 'omics' technologies now provides important proof of biochemical predictions and creates new opportunities for understanding cellular functional architecture.

A new study fulfills a central goal of post-genomic medicine, the treatment of inherited loss-of-function disorders not by correcting a genetic mutation but by augmenting the efficiency with which the nascent mutant gene product undergoes conformational maturation and is deployed to its site of action.

Bacterial polysaccharides exhibit remarkable structural diversity and play critical roles in the biology of their producing organisms. A recent study defines the minimal machinery for polymerization in a widely disseminated assembly pathway.

The ability to degrade atrazine has been engineered in a strain of Escherichia coli capable of responding specifically to the presence of the herbicide. A chemical biology approach generated an atrazine-sensitive riboswitch enabling a cellular response to occur only in the presence of the toxin.

Drugs identified in high-content screens are often difficult to link to the cellular target, especially when multiple signaling pathways impinge on the phenotypic endpoint. A chemical-genetic approach in fruit fly cells now greatly improves the prioritization of drug hits by directing the screen toward a single pathway.

COX-2 is the enzyme largely responsible for causing inflammation, a common mechanism of disease. A study now reports that derivatives generated by COX-2 from naturally occurring ω-3 fatty acids are anti-inflammatory mediators.

Bacteria resistant to glycopeptides such as vancomycin sense the drugs and escape killing by remodeling synthesis of the cell wall target. A photoaffinity probe shows that induction of resistance relies on direct drug recognition by a glycopeptide sensor.

Functionally coupled motions between the voltage-sensing and the phosphatidylinositol phosphatase domains of the sea squirt protein Ci-VSP is mediated by PI(4,5)P₂ binding to the intervening linker, shedding light on the function of an unusual voltage-sensing protein.

The level of an individual protein in cells treated with combinations of drugs is best explained by simple linear superposition of the protein levels in response to single drugs. This finding may facilitate rational design of higher order drug combinations.

The buildup of toxic intermediates during lignocellulose pretreatment limits the utility of this abundant biomass for biofuel production. A recent study on the degradation pathways of two of the most hazardous toxins, furfural and HMF, now paves the way for mechanism-based enhancements of biodetoxification efficiency.

NMR-measured order parameters of methyl groups can be used to quantify the entropy of protein conformational change associated with calmodulin–peptide ligand interactions. This conformational entropy is a major contributor to the affinity of calmodulin interactions and can now be determined experimentally on a per-atom basis.

In most archaea, the enzyme TiaS post-transcriptionally modifies a cytidine in the anticodon of tRNA^Ile, converting it to agmatidine (agm²C or C⁺). This unique nucleoside allows translation at the AUA isoleucine codon and prevents misreading of the AUG methionine codon.

Evolutionary conservation of TRPA1 underlies sensation of reactive noxious chemicals from flies to humans.

The final steps in the biosynthetic pathway to the morphine alkaloids have been revealed with the characterization of two key enzymes. In addition to the widely exploited parent compound, these new O-demethylases control metabolic flux to pharmaceutically useful opioid precursors.

Many kinase inhibitors for cancer therapy are rather nonselective, and their cellular mechanisms of action are incompletely understood. A nested chemical proteomics and chemical genetics strategy reveals which cellular targets of the clinical kinase inhibitor dasatinib functionally relate to its anti-oncogenic activity.

Organic synthesis plays a leading role in the discovery of small molecules for the exploration of biological systems. Therefore, the development of efficient strategies for the preparation of these molecules is a necessary aspect of the small-molecule approach to chemical biology.