Articles in 2011

GPCRs are known to initiate a variety of signaling pathways, but their full reach in coordinating cellular events is unknown. Live cell imaging using label-free and fluorescence assays to monitor the effects of GPCR ligands now surprisingly connects GPCR networks to nucleotide metabolism.

An evolutionary algorithm predicts anti-inflammatory drug combinations that have synergistic effects on IL-1β expression more efficiently than would empirical approaches of testing drug combinations individually.

Trafficking G proteins between membranes is essential for their signaling activity. Structural and biochemical studies on the farnesylated G protein Rheb and the guanine nucleotide–dissociation inhibitor (GDI)-like PDEδ suggest an allosteric mechanism for Rheb release and identify a bona fide GDI-displacement factor (GDF).

Cells must coordinate nutrient uptake for balanced growth, but the mechanism by which this occurs was unknown. Flux measurements and biochemical assays now identify α-ketoglutarate as the key signal in this process that accumulates upon nitrogen limitation and inhibits an enzyme involved in glucose transport.

Peptidic natural products are theoretically amenable to characterization by mass spectrometry, but proteomics programs are not trained to discover these compounds. A new strategy uses mass spectrometry and bioinformatics iteratively to rapidly identify both ribosomal and nonribosomal sequences, yielding multiple new compounds.

Investigations into kanamycin biosynthesis and identification of new pathway intermediates surprisingly point to the substrate specificity of two glycosyltransferases as controlling flux into parallel pathways, allowing changes to product profiles and structures by varying these gatekeeper enzymes.

Complex polysaccharides are generally thought not to have a defined carbohydrate sequence because their synthesis is not template-directed. Detailed mass spectrometry of bikunin now counters this dogma, showing that each molecular weight species consists of only a single sequence.

Rapid reversible inhibitors of the oxygenation activity of COX-2, including ibuprofen and naproxen, selectively inhibit the enzyme with endocannabinoid 2-AG substrates but not with arachidonic acid, and this substrate-selective inhibition may be important for the analgesic activity of the drugs.

A chemical-genetic study predicts mechanisms of resistance to PI3K inhibitors. Activation of NOTCH signaling, which leads to c-MYC expression, can overcome cancer cell dependency on PI3K signaling for growth. NOTCH and PI3K have not previously been linked in breast cancer.

Mono- and digalactosyldiacylglycerols (MGDGs and DGDGs) are glycolipids that are central to plant metabolism and photosynthetic membrane biogenesis. Galvestine-1, a small molecule inhibitor of MGDG synthases that was identified in a high-throughput chemical screen in Arabidopsis thaliana, reveals a new role for these galactolipids in pollen-tube development.

A single trimethylated species is obtained in an on-resin N-methylation reaction of a cyclic hexapeptide. This regioselectivity is driven by conformation and the presence of intramolecular hydrogen bonds, and is correlated with membrane permeability of the peptides.

The inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes. Affinity purification using PU-H71 reveals cancer-specific protein networks in chronic myeloid leukemia and that the abundance of tumor-specific Hsp90 clients in cells can predict sensitivity to Hsp90 inhibitors.

Nonsense suppression, or reassigning stop codons to encode for other amino acids, offers a method for expanding the genetic code of proteins. Deletion of release factor 1 in an Escherichia coli strain enables the incorporation of non-natural amino acids into proteins at multiple sites.

A virtual screen of the GPCR D3R based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor once it became available both identified new ligands with verified activities.

A screen for compounds that alleviate the inhibitory effect of influenza NS1 on host gene expression and suppress viral toxicity found naphthalimides that could upregulate REDD1, an mTORC1 inhibitor, revealing that viruses inhibit REDD1 to activate the mTORC1 pathway.

A transposon-generated mutation strategy used to find targets of eight antibacterial compounds and compound combinations in Staphylococcus aureus identifies known targets as well as new mechanisms of resistance.

The ribosomal incorporation of a new, more flexible photocrosslinking amino acid allows the identification of client proteins for a chaperone that works during acid stress as well as the discovery of a chaperone-cooperation mechanism that enhances protein refolding upon pH neutralization.

The redox-sensitive TRP channel TRPA1 is activated in hyperoxic and hypoxic conditions directly through modification of cysteine residues by O₂ and indirectly through prolyl hydroxylation by PHDs, enzymes related to the hypoxia-inducible factor HIF-1, thus helping to explain how O₂ is sensed by sensory and vagal neurons.

Monitoring preassembly of the G protein–coupled receptor M3 muscarinic acetylcholine receptor M3R–G_q heterotrimers by FRAP reveals that agonist- and antagonist-insensitive preassembly of inactive-state complexes via a polybasic motif in M3R increases the sensitivity and accelerates the onset of GPCR signaling.

The aromatic compound rifamycin SV binds to expanded and partially compact assembly intermediates and inhibits amyloid fibril formation of β₂-microglobulin by diverting assembly toward soluble, toxic spherical aggregates lacking the classical structure of amyloid.