Articles in 2015

Protein methyltransferase PRMT5 symmetrically dimethylates arginine residues in proteins, including histones, and has been associated with tumorigenesis. The identification of EPZ015666 as a potent chemical probe of PRMT5 could promote understanding of the role of PRMT5 in human disease both in cells and in vivo.

Retinoid isomerase is a critical enzyme in the conversion of retinyl esters to 11-cis-retinol, a key step in the regeneration of visual pigments that mediate light perception. Structural, biochemical and modeling data using substrate analogs explain how this unusual reaction proceeds.

Drug-target residence time is viewed as a predictor of the clinical efficacy of small-molecule drugs. A pharmacodynamic model, taking into account the target binding kinetics of antibacterial compounds, leads to accurate predictions of cellular and in vivo efficacies of the inhibitors.

The natural product didemnin B inhibits PPT1 and the antiapoptotic protein Mcl-1 in particular types of cancer cells containing a unique genetic profile that correlates with drug sensitivity.

An siRNA screen for genes that suppress mutant huntingtin toxicity in both mammalian cells and Drosophila identifies glutaminyl cyclase (QPCT). Newly generated small-molecule inhibitors further identify QPCT as a druggable target for Huntington′s disease.

Genetic, biochemical and bioinformatic data define a pathway in Archaea that links the ribose moieties of nucleosides to central carbon metabolism, substituting for the classical pentose phosphate pathway found in Bacteria and Eukarya.

The orphan nuclear receptor Nur77 blocks inflammation through inhibition of p65 DNA binding and is suppressed by p38α-mediated phosphorylation. A small-molecule compound, PDNPA, disrupts p38α-Nur77 interactions and alleviates mouse models of sepsis.

Bioconjugation methods enable a variety of applications, but it remains difficult to modify many proteins in a single location with a single functional group. A serendipitous discovery of aldehyde reactivity now leads to reagents for the selective labeling of protein N termini under mild conditions.

The lack of existing tools has made it difficult to detect and quantify methionine sulfoxide in cells. The introduction of the MetSOx and MetROx fluorescent sensors allows detection of stereospecific forms of methionine sulfoxide in cells.

O-GlcNAcylation is a known post-translational modification, but analysis of nascent proteins now demonstrates that it also occurs during translation, preventing proteolytic degradation of modified proteins by blocking ubiquitination.

Several GPCRs have ligands that act as pharmacological chaperones that rescue function of mutated receptors. This formed the basis of a screening strategy to identify new ligands for Frizzled4 that act allosterically at an effector domain to inhibit β-catenin signaling.

The discovery of two new types of enzymes that act in tandem within the spirotetramate biosynthetic pathway to catalyze [4+2] cycloadditions offers new opportunities for mechanistic investigations of potential Diels-Alderases.

Technologies that bias GPCR expression for formation of heterodimers show that, when heterodimerized, α_2C-AR and AT-1R exhibit atypical G_s-cAMP-PKA signaling upon ligand stimulation compared to either parent receptor expressed alone and mimic activation associated with arterial hypertension.

Light-harvesting complexes (LHCs) manage energy flux into photosynthesis and dissipate excess light energy. The demonstration of dissipative energy transfer from chlorophyll-a to β-carotene in cyanobacterial high light–inducible proteins provides a mechanistic model for similar processes in LHCs.

A screen for compounds that inhibit disulfide bond formation in β-galactosidase in Escherichia coli found inhibitors of the membrane enzyme DsbB. Given the importance of DsbB in bacterial virulence, the inhibitors are potentially useful as antibacterials.

N-linked glycosylation of a conserved arginine in the translation elongation factor EF-P by a newly discovered rhamnosyltransferase EarP is needed to rescue ribosomal stalling at polyproline-encoding sequences in β-proteobacteria and other species.

A series of designed peptides call the sphere of influence of the helix macrodipole into question, showing that the favorable rotamers allowed by K→E hydrogen bonds beat out the entropically penalized but macrodipole-aligned E→K hydrogen bonds.

Small unilamellar vesicles composed of the negatively charged lipid DMPS enhance the aggregation of the Lewy Body disease protein α-synuclein by increasing the rate of primary nucleation by a thousandfold.

RNA has been used in a variety of synthetic biology circuits but never as a transcriptional activator. Two design strategies using synthetic and natural sequences now lead to RNA activators, enabling RNA-only logic gates.

Reversible transcriptional repressors are built with TALE proteins on the basis of steric hindrance of a new promoter architecture in an RNA-sensitive manner, enabling applications in mammalian cells such as classification of cancerous versus noncancerous cells.