Volume 12 Issue 12, December 2016

Interfacing photosynthetic proteins and electrodes for investigating light-induced charge separation remains challenging. The discovery of a competing charge transfer pathway through the light-harvesting antenna defines new design requirements for electrode modification.

Through simultaneous binding to more than one site in a single protein, multivalent small molecules can achieve huge increases in potency. This 'avidity effect' has been demonstrated in BET bromodomain-containing proteins with bivalent probes that represent some of the most potent BET inhibitors to date.

Three newly identified endogenous ligands of the nuclear receptor PPARα—hydroxydimethylbutyrate, hexadecanamide and octadecenamide—are implicated in the noncanonical activity of PPARα in synaptic function and hippocampal plasticity.

A proteomic approach in Saccharomyces cerevisiae identifies cytochrome b reductase (Cbr1) as an NADH-dependent electron donor for diphthamide biosynthesis 3 (Dph3), a protein that serves as an electron source for diphthamide biosynthesis and tRNA modification.

ADP-ribosylation is a post-translational protein modification that regulates numerous cellular pathways. An approach involving histone purification, partial filter-aided digestion and ETD mass spectrometry reveals that serine residues in histone proteins are ADP-ribosylated.

Unlike their bacterial counterparts, fungal nonribosomal peptide synthetases utilize a terminal condensation-like (C_T) domain to form macrocycles, details of which are illuminated by structures of a C_T domain and neighboring thiolation domain.

The synthetic bioinformatic natural products (syn-BNPs) approach identifies putative natural products that are validated directly by independent synthesis. Its application led to the identification of humimycins, non-ribosomal peptides that have antimicrobial activity in mice.

Two programs, GRAPE and GARLIC, work together to first predict biosynthetic gene clusters responsible for the production of polyketides and nonribosomal peptides, then link sequenced gene clusters to known and unknown natural products.

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.

A high-throughput screen identifies NGI-1 as an inhibitor of oligosaccharyltransferase, preventing transfer of N-linked glycans to proteins. NGI-1 blocked EGFR signaling in non-small-cell lung cancer cell lines and promoted cell-cycle arrest and senescence.

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.

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.

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.

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.

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.

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.

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.

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.

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.