Articles in 2016

Arachidonyl and adrenoyl PE phospholipids generated by ACSL4, an acyl-CoA synthase, are doubly or triply oxidized by lipoxygenases and other iron-containing sources of oxidation to promote ferroptotic cell death.

A monobody was identified that binds to an allosteric lobe at the α4-β6-α5 interface to block H- and K-RAS signaling and transformation by disrupting RAS dimerization and nanoclustering.

Inhibitors of the post-proline-cleaving serine proteases DPP8 and DPP9 trigger a lytic form of programmed cell death called pyroptosis by activating pro-caspase-1 without autoproteolysis.

Carbapenem β-lactam antibiotics target non-classical transpeptidases, the L,D-transpeptidases, which act in an alternative Mycobacterium tuberculosis peptidoglycan synthesis pathway, informing the design of evolved carbapenems with improved antibacterial activity.

Aggregated mass spectral data by consortia such as the Global Natural Products Social (GNPS) molecular networking infrastructure enable natural product discovery. DEREPLICATOR, validated on peptidic natural products, is a computational tool to identify known metabolites in complex samples.

A systems-level look at the activation of joint synovial fibroblasts in rheumatoid arthritis patients in response to different activators and therapeutic kinase inhibitors shows that multivariate inhibitor effects depend on the nature of the activator, not on the disease state per se.

Structural and biochemical studies of the histone acetyltransferase p300 in complex with acyl-CoA substrates reveal a lysine binding channel that accommodates a particular chain length to mediate efficient histone modification.

Structural insights demonstrating small-molecule-mediated dimerization of BRD4 bromodomains led to the development of biBET, a compound that potently inhibits BRD4–acetyl-lysine interactions by bivalent binding to tandem bromodomains.

A fragment-based design approach identifies reversible inhibitors targeting human protease complement factor D (FD), which is required for amplification of complement C3 signaling. FD inhibitors act as systemic regulators of complement activation in vivo.

Structural and biophysical analysis of the histone acetyltransferase MOZ double PHD finger (DPF) domain reveal that DPF exhibits strong binding preference for crotonylated Lys14 in histone H3 (H3K14) and are co-localized in cells.

Targeting the acetyllysine ‘reader’ activity of BET family transcriptional coactivators has emerged as an anticancer modality. A new class of dimeric JQ1 derivatives displays enhanced potency for bivalent targeting of tandem bromodomains in BET proteins.

Three endogenous ligands of the nuclear receptor PPARα—hydroxydimethylbutyrate, hexadecanamide, and octadecenamide—are potentially responsible for noncanonical activity of PPARα in synaptic function and hippocampal plasticity.

Within polypeptides, C5 hydrogen bonds form between the amide proton and carbonyl oxygen of the same residue. This intraresidue interaction stabilizes β-sheets in particular and is widespread throughout structurally characterized proteins.

Detailed computational and structural analysis of a large data set of non-peptidic macrocycles revealed particular functional groups, substituents and molecular properties that are critical for dictating cellular permeability.

A metabolomics analysis finds that host glycolysis, fatty acid oxidation, the urea cycle, cholesterol biosynthesis and oxidative phosphorylation are modified by hepatitis C virus infection. These effects are mediated through nuclear receptor transcription factors HNF4α, PPARα and FXR.

SF2312, a phosphonate antibiotic, directly binds and inhibits the activity of the glycolytic enzyme enolase and is selectively toxic to ENO1-deleted glioma cells through inhibition of glycolysis and depletion of ATP.

When coupled to electrodes, the photosystem II complex can participate in a photo-induced oxygen reduction mechanism via chlorophyll a pigments that competes against the desired water-oxidation charge transfer pathway.

The Cre–loxP recombination system is a classical tool for targeted genetic engineering. Blue-light-induced dimerization of a split Cre system enables efficient light-controlled DNA integration at loxP sites within cells and in living mouse tissues.

5-nitroanthranilic acid aminohydrolase catalyzes the first step in biodegradation of a nitroaromatic compound via a nucleophilic aromatic substitution mechanism with an unusual substrate-assisted metal loading step.

Functional annotation of bacterial thiamine transporters via a generalizable synthetic biology approach using riboswitches identifies a novel family of thiamine-uptake systems from prokaryotic metagenomes, including PnuT, as well as two novel xanthine importers.