Research articles

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.

A quantitative covalent labeling strategy reveals that multiple ligand-specific conformational states are present in the G protein–coupled β₂-adrenergic receptor. Their existence may underlie 'biased agonism', which describes the differential abilities of agonists to activate distinct signaling mechanisms downstream of GPCRs.

A systematic analysis of possible substrates for reverse glycosyltransferase reactions reveals thermodynamically favored pathways to the traditional 'activated' sugar donors, enabling high-yielding enzymatically coupled sugar transfers and a general colorimetric assay for sugar nucleotide formation and utilization.

The first high-resolution structures of transaldolase with bound intermediates both define active site residues that necessitate a revision of the current reaction pathway and point to a high-energy intermediate structure and protein conformational changes as mechanisms to promote product formation.

PoxA is a lysyl-tRNA synthetase paralog that post-translationally modifies elongation factor P (EF-P) with a lysine moiety. Further biochemical analysis reveals that (R)-β-lysine, rather than the more abundant α-amino acid, is the preferred substrate for PoxA.

Purine base binding specificity in adenine and guanine riboswitches is governed primarily by specific base pairing interactions in the ligand-binding site. A series of 2′-deoxyguanosine riboswitch structures reveals remodeling of the ligand-binding site and remote regions of the structure to accommodate the sugar moiety of the nucleoside substrate.

The combination of several biochemical analyses, including determination of kinetic isotope effects and linear free energy relationships, offer the first detailed insights into a natural S_Ni-like reaction mechanism and provide compelling evidence for a frontal nucleophilic substitution in a retaining glycosyltransferase.

The identification of cellular targets for natural products that potently inhibit the growth of cancer cell lines implicates oxysterol-binding proteins in the growth of cancer cells. These natural products, termed ORPphilins, also affect sphingomyelin biosynthesis.

Mussel adhesion depends on secreted dopa-modified proteins, but the dopa groups are prone to oxidation, which decreases their stickiness. A second mussel protein is now shown to regulate the redox state of these adhesive groups by coupling thiol oxidation to dopa reduction.

FlAsH fluorescence and thioflavin-to-FlAsH FRET are used to distinguish amyloid-β oligomer formation from fibril formation, supporting rapid oligomer formation prior to fibril formation—consistent with a nucleated conformational conversion mechanism—that can be modulated by certain Alzheimer's disease–linked mutations or lipids.

Phytophthora use mating hormones to mediate reproduction between two distinct strains, but only one of the hormones has been structurally characterized. The isolation and analysis of the elusive second hormone demonstrates that the two hormones are biosynthetically linked and universally used across Phytophthora species.

Salt bridges between positively charged residues within the S4 transmembrane segment of the voltage-sensing potassium channel, Shaker, and acidic residues in S2 and S3 segments are not necessary during channel gating; rather, two of the acidic residues may occupy a hydrophilic water-filled vestibule that creates an energetically favorable environment for S4 movement during channel gating.

Based on a BRET readout, dopamine D2 receptor agonist NPA is more potent at activating Gα_i when the D2 receptor forms a heteromer with the related D1 receptor than if it forms D2 receptor homomers, suggesting that GPCR heteromerization can result in functional selectivity.

A stabilized helical peptide mimic of a key helix from the guanine nucleotide exchange factor Sos interferes with Ras-Sos interaction and inhibits Ras signaling in response to receptor tyrosine kinase activation.