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EZH2 is a protein methyltransferase component of the polycomb repressive complex 2 (PRC2) that installs the H3K27me3 chromatin mark. EPZ005687 inhibits EZH2 function and H3K27 trimethylation in cells and selectively kills lymphoma cells that require EZH2 for proliferation.
A compound derived from a structure-based screen binds to an allosteric site that includes residues of both the helicase and protease domains of HCV NS3, stabilizing an inactive conformation and inhibiting viral replication.
A systems-pharmacology approach reveals that the combined off-target activity of two kinase inhibitors that impedes MAPK signaling to decrease expression of Myc target genes increases apoptosis in CML cells containing gatekeeper mutations in BCR-ABL.
Ferritin controls iron concentrations by storing Fe(III), but the mechanism by which Fe(II) is bound and trafficked into the protein core after oxidation remains controversial. Spectroscopic methods in combination with labeling and competition assays now define a mechanism conserved from archaea to humans.
Mass spectrometric profiling has revealed S-geranylation as a new tRNA modification and identified SelU as the tailoring enzyme in bacterial cells. Nucleotide S-geranylation was found in the anticodon of several tRNAs and regulates translational frameshifting and codon usage.
A small molecule that disrupts interaction between Nur77 and LKB1 leads to LKB1 exit from the nucleus to activate cytoplasmic AMPK and, ultimately, reduces blood glucose and insulin in diabetic mice.
A new global annotation strategy combines sequence identity and genomic context to provide probabilities for all metabolic assignments in a given species. Application of this method leads to multiple new annotations and validation of three enzymatic activities in B. subtilis.
Tafazzin, the mitochondrial transacylase that is deficient in Barth syndrome, selects lipid substrates in the inverted hexagonal phase but does not react with bilayer lipids.
Expanding the bacterial toxin-antitoxin system classes to a fifth class, GhoST was found to be involved in maintenance of persister cells, dormant cells that are tolerant of antibiotics. GhoS is the antitoxin, an endoribonuclease that cleaves the toxin mRNA ghoT, whose gene product is a membrane-lytic protein.
C18-ceramide mediates lethal autophagy by anchoring LC3B-II (lipidated LC3) to mitochondrial membranes during mitochondrial fission and thereby recruiting autophagosomes.
A small-molecule activator specific for PKM2 binds to a site distinct from the endogenous activator fructose-1,6-bisphosphate, promoting tetramerization and constitutive activation of PKM2, to inhibit xenograft tumor growth in mice.
The reconstitution of two fungal NRPSs provides the first biochemical evidence that these assembly lines use a condensation-like domain to complete the synthesis of cyclic natural products instead of the thioesterase domain used in bacterial species.
DNA damage products influence DNA replication but also may induce stalling or mutagenesis during transcription. A competitive transcription and adduct bypass assay provides a new approach for assessing the transcriptional effects of DNA lesions and links transcriptional arrest of several lesions to nucleotide excision repair pathways.
The plant hormone auxin affects many aspects of root development, including lateral root branching. A high-throughput screen in Arabidopsis thaliana has led to the identification of naxillin, a non-auxin chemical probe that enhances lateral root branching and has revealed an important role of the root cap in regulating this process.
Discovery of the native activity of the ~60,000 putative glycosyltransferases remains a substantial challenge. A high-throughput, label-free method drastically speeds this process, with assays of 85 enzymes, 24 acceptors and 7 donors returning functions for four new proteins.
Single-molecule imaging reveals that GPI-anchored proteins in the plasma membrane form homodimer rafts via ectodomain protein interactions. Raft-lipid interactions stabilize higher order oligomers, which trigger intracellular signaling upon ligand binding.
A study of three synthetases involved in streptothricin biosynthesis demonstrates roles for two A domains in activating lysine, with one A domain transferring lysine to a carrier T domain and the second directly catalyzing amide bond formation to form a growing lysine oligopeptide.
Application of a new thermal light scattering technique to quantitatively analyze nearly 150 mutants of the rhomboid intramembrane protease GlpG, coupled with thermodynamic measurements and protease assays, reveals how interactions throughout the molecule collaborate to support enzyme structure and function.
Bacterial siderophores are known to bind various metals in vitro but are generally thought of as iron chelators in vivo. MS now demonstrates that yersiniabactin binds copper in vivo, with yersiniabactin expression correlated to bacterial fitness.