Volume 12 Issue 10, October 2016

Stapled helices are promising compounds for inhibiting intracellular protein–protein interactions, but the discovery of peptides with the key property of cellular uptake has taken place largely through trial and error. A new study defines physicochemical parameters for designing hydrocarbon-stapled helices with a greater likelihood of cellular uptake.

A new study reports THZ531 as a covalent CDK12/CDK13 inhibitor affecting transcription. Application of the compound in cells decreases transcription elongation of DNA damage response genes and key super-enhancer-associated transcription factor genes, with important implications for targeted cancer therapy.

TALE proteins search for target sequences along a DNA substrate in a uniquely one-dimensional and non-rotating fashion.

Scientists find that oxidation of methionine induces favorable interactions with aromatic groups in proteins, contrary to conventional wisdom, providing new molecular insight into the structural and biological impact of methionine oxidation.

Nemamides are hybrid polyketide–nonribosomal peptide natural products that were identified by metabolomics profiling in Caenorhabditis elegans and are involved in the organism's survival response to nutrient-deficient conditions.

Variations in pathway off-loading and module skipping within a hybrid polyketide synthase–nonribosomal peptide synthetase lead to the production of a collection of precursors to colibactin, a genotoxic compound produced by gut bacteria.

Adeno-associated viral delivery of an orthogonal tRNA synthetase-tRNA system enables the encoded incorporation of non-natural amino acids into proteins in neuronal cells, in brain slices and in living mice.

The application of a potent lactate dehydrogenase (LDHA) inhibitor GNE-140 on pancreatic cancer cells revealed that resistance to GNE-140 is attributable to an AMPK–mTOR–S6K-mediated switch in utilization from glycolysis to oxidative phosphorylation.

Analysis of the hydrolysis kinetics of strigolactone receptors using enzyme-activated fluorescent probes revealed that the catalytic triad histidine of the receptor forms a covalent interaction with the strigolactone hydrolysis product, the D ring.

A cyclobutane compound competitively inhibits the activity of androgen receptors (AR) containing antiandrogen-resistant mutations through stabilization of the receptor in an apo-like conformation and preventing AR nuclear entry.

The modification of Cdc42 with a FRET binding antenna (GDI.Cdc42 FLARE) enables detection of Cdc42 binding to guanine-nucleotide dissociation inhibitor (GDI) and Cdc42 activation with improved spatial-temporal resolution during cellular protrusion and retraction.

The LARGE glycosyltransferase generates a repeating disaccharide on α-dystroglycan, an extracellular matrix receptor essential for muscle function. A structural study defines a unique binding mode between the LARGE-generated oligosaccharide and the matrix protein laminin.

Structural, enzymatic and cellular target engagement studies reveal the mechanism of action by N-hydroxyurea small molecule inhibitors of the DNA repair enzyme, human flap endonuclease-1 (FEN1) that prevent cleavage of DNA flaps in cancer cells.

A biosensor based on the GABA_A receptor with a readout consisting of quenching and recovery of biomolecular fluorescence in live cells is used in a screen to identify new interacting ligands for the receptor benzodiazepine site.

A single-molecule approach demonstrates that TALEs scan DNA using a unique ‘zip-line’ mechanism wherein the TALEs move without rotating along the DNA helix, yet the DNA remains threaded through the loosely wrapped TALE.

A high-throughput screen using a mass-spectrometry-based assay results in the identification of LRE1 as an inhibitor of HCO₃⁻/Ca²⁺-regulated soluble adenylyl cyclase activity. LRE1 interacts with the HCO₃⁻ binding site (BBS) to block cAMP formation.

Detailed biophysical, microscopy, and statistical analyses of hydrocarbon-stapled peptide variants revealed how a combination of critical parameters such as hydrophobicity, α-helicity and isoelectric point influence cellular permeability.

Probes based on the photoactive yellow protein tag for monitoring the consequences of glycosylation on GLUT4 traffic reveal that glycosylation is important for plasma membrane retention of the glucose transporter.

A combination of statistical analysis, quantum mechanics calculations and biophysical analytical approaches shows that methionine oxidation increases its interactions with aromatic side chains, interactions that are important for intraprotein and interprotein interactions.

Biochemical and genetic strategies demonstrate that the antifungal natural product beauvericin targets both multidrug efflux and TOR signaling to limit drug resistance and to sensitize resistant pathogens to drug treatment during infection.

A small molecule inhibits CDK12 and CDK13 activity through covalent modification of Cys residues and reveals a role of the two kinases in regulating Pol II processivity and super-enhancer-driven transcription factor and DNA damage response gene expression.