Research articles

The squid beak displays a 200-fold stiffness gradient across its length. A battery of experiments, including ‘omics analysis and rheological measurements, now identifies two protein families that infiltrate and cross-link a porous chitin network to generate variable stiffness.

A computational analysis of cryo-EM data defines the binding mode of capsaicin on TRPV1. A mutational analysis validates these findings, showing specific van der Waals and hydrogen-bonding interactions with the head, neck and tail regions of capsaicin.

An amphotericin antifungal that is less toxic to human cells due to its increased capacity for binding the fungal ergosterol over the human cholesterol can still evade resistance mechanisms, challenging the resistance-toxicity yin-yang of antimicrobials.

A newly engineered phosphoserine synthetase/tRNA pair allows quantitative insertion of phosphoserine or, when coupled with metabolic rewiring, a non-hydrolyzable analog into protein sequences, leading to high yields of modified constructs for functional analysis.

A high-throughput screen identified a small molecule that promoted inclusion of SMN2 exon 7, increased SMN2 protein levels and extended survival in a SMA mouse model through stabilization of the interaction between SMN2 pre-mRNA and U1 snRNP complex.

Structural changes in the capping groups of inverted cyanoacrylamide-based kinase inhibitors resulted in alterations in residence time, with some compounds exhibiting sustained pharmacological effects in vivo.

NO₂⁻ has been viewed primarily as a reservoir for NO and NO-modified species, activated by acids or metal catalysis. Isotopic labeling of NO and NO₂⁻ modifications in vitro and in vivo now demonstrates that NO₂⁻ also participates directly in these reactions through a symmetric N₂O₃ intermediate.

The biosynthesis of benzylisoquinoline alkaloids such as morphine requires tyrosine oxidases, which are prone to overoxidation. A colorimetric readout that co-opts betaxanthin enzymes now enables discovery of an improved oxidase that, with other enzymes, makes reticuline in yeast.

Topoisomerase inhibitors are genome-targeting drugs that induce DNA double-strand breaks or evict histones at sites of action. Genomic mapping of their target sites by ChIP-Seq and FAIRE-Seq and integration with ENCODE data identifies the target specificities of topoisomerase inhibitors and suggests ways to optimize their therapeutic properties.

Fusion of HIV with target membranes via the HIV fusion peptide requires phase separation among lipids as well as phase heterogeneity because the fusion is biased toward the boundary between regions of ordered (so-called rafts) and disordered lipids.

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.

The use of a presumed chemical intermediate in the mechanism of enoyl thioester reductase enables the identification of the long-sought proton donor and the rational redesign of enzyme stereoselectivity.

Post-translational regulation of Cas9 activity may improve the specificity of genomic targeting. A modified version of Cas9 with an insertion of a small molecule–regulated intein allows temporal control of Cas9 activity and reduces off-target activity.

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.