Brief Communications in 2011

Studies elucidating the role of p38α MAPK in diverse biological processes are limited by the lack of a specific inhibitor. Skepinone-L is a highly selective ATP-competitive inhibitor of p38 with excellent potency in vivo.

A cheminformatics approach helps identify proteins such as GPCRs, ion channels and kinases that are targeted by small molecules that give phenotypes in a zebrafish behavioral assay.

Dafadines, identified in a screen for compounds that induce the dauer phenotype in C. elegans, also promote longevity in adult worms, with both phenotypes occurring through inhibition of DAF-9, a cytochrome P450 involved in the insulin signaling pathway.

N6-Methyladenosine is an abundant nucleoside in cellular mRNA that undergoes demethylation under physiological conditions by fat mass and obesity-associated protein (FTO). This new pathway suggests that RNA modifications can be reversible and potentially have an impact on RNA metabolism.

Histidine kinase 4 from Arabidopsis thaliana (AHK4) is a membrane-bound receptor for cytokinins, a class of plant hormones involved in growth, development and defense. Crystal structures of the AHK4 sensor domain in complex with various natural and synthetic cytokinins reveal important features of ligand recognition by this cytokinin receptor.

Cleavage of peptide precursors is well known for ribosomally produced sequences. Investigation of xenocoumacin biosynthesis now points to a similar function in nonribosomal peptide synthesis clusters, explaining one source of mismatches between genetic and chemical information.

An untargeted metabolomics approach identifies C14 phosphatidylcholines (PCs) as specific cellular medium-chain substrates of the lipase ABHD3, as well as C5–C8 short-chain PCs including oxidized pro-atherosclerotic and pro-apoptotic PC phospholipids.

PoxA is a lysyl-tRNA synthetase paralog that post-translationally modifies elongation factor P (EF-P) with a lysine moiety. Further biochemical analysis reveals that (R)-β-lysine, rather than the more abundant α-amino acid, is the preferred substrate for PoxA.

Mussel adhesion depends on secreted dopa-modified proteins, but the dopa groups are prone to oxidation, which decreases their stickiness. A second mussel protein is now shown to regulate the redox state of these adhesive groups by coupling thiol oxidation to dopa reduction.

Phytophthora use mating hormones to mediate reproduction between two distinct strains, but only one of the hormones has been structurally characterized. The isolation and analysis of the elusive second hormone demonstrates that the two hormones are biosynthetically linked and universally used across Phytophthora species.

A stabilized helical peptide mimic of a key helix from the guanine nucleotide exchange factor Sos interferes with Ras-Sos interaction and inhibits Ras signaling in response to receptor tyrosine kinase activation.

FrsA is responsible for the metabolic switch between fermentation and respiration, but the basis for this function has been unknown. Biochemical, structural and in vivo analyses now demonstrate that FrsA is a cofactor-independent pyruvate decarboxylase and thus directly controls carbon flux.

Two crystal structures of a three-domain class II diterpene cyclase with substrate and product analogs provide new insights into the mechanistic pathway of this enzyme and illuminate evolutionary and functional relationships within terpenoid biosynthesis more generally.

PUF proteins bind RNA sequences through specific interactions between PUF repeats and adenine, guanine and uracil bases. A directed evolution approach has identified new PUF repeats that specifically bind cytosine, which enables the recognition of diverse RNA sequences by engineered PUF proteins.

D-Ornithine has been used as a supplement under the assumption that it increases production of pyrrolysine-containing proteins, but detailed characterization and investigations of pyrrolysine biosynthesis now demonstrate these modified proteins contain an entirely different amino acid.

The systematic exploration of off-patent drugs in combination with the antibiotic minocycline uncovers unexpected synergies in antibiotic-nonantibiotic pairs. These interactions are exemplified by the nonantibiotic loperamide, which finds a new function in facilitating tetracycline uptake.

A specific and potent inhibitor of the DNA damage response kinase ATR can exploit synthetic lethality between ATR and the related kinase ATM to sensitize ATM-defective cancer cells to ionizing radiation and DNA-damaging drugs.

Experiments on reconstituted liposomes and sperm capacitation, an activation process involving the reduction in membrane cholesterol content and subsequent exposure of surface carbohydrate, show that cholesterol masks the presentation of glycolipid head groups by inducing a conformational shift in the glycan moiety.

A selective, short-acting agonist for the sphingosine-1-phosphate receptor S1P₁ and GFP-S1P₁ knock-in mouse model are used to show that both receptor degradation and receptor reserve underlie the mechanisms of lymphocyte sequestration by agonists.

The ribosomal production of two short peptides conserved across divergent plant species unexpectedly uses an open reading frame for an unrelated protein, albumin, as well as albumin processing–machinery to create mature cyclic sequences.