Research articles

Numerous aerobic bacteria depend on glutathione but are lacking the first enzyme in its biosynthetic pathway. An evolutionary experiment identifies a likely natural route to compensate for this loss through mutations in two enzymes in proline biosynthesis.

A new fluorescent indicator reveals that a ROS-producing NADPH oxidase generates H₂O₂, normally associated with pathological conditions such as neurodegeneration, in neural stem cells where it regulates Akt phosphorylation and normal cell proliferation.

Biomimetic divalent ligands based on the PDZ domain–binding motifs from the AMPA receptor auxiliary subunit Stargazin disrupt the receptor's interaction with the scaffold protein PSD-95 and show that AMPARs are stabilized at synapses by engaging in multivalent interactions with PDZ domain-containing proteins.

Identifying the cellular targets of small molecules remains a central challenge of chemical biology. The application of an RNAi-based functional genomics approach permitted the clustering of drugs with related targets by 'shRNA signatures', which served as a basis set to assign modes of action to compounds with unknown targets.

A chemical genetics approach identifies the Raf-MEK-ERK signaling system downstream of PKC in formation of the antimicrobial cell structures called neutrophil extracellular traps.

Post-translational modifications are critical to protein structure and function. Mass spectrometry, antibody pulldowns and other lines of evidence now establish the presence of lysine succinylation across numerous proteins and species.

Structural analysis by NMR reveals that the Gly237-Pro238 bond of the signaling protein Crk in the cis form stabilizes an autoinhibited conformation between two tandem SH3 domains, whereas the trans form promotes an activated conformation for Abl kinase binding.

A potent hepatitis C virus protease protein inhibitor forms an irreversible covalent bond to a virally conserved noncatalytic cysteine in the protease substrate-binding pocket identified in a bioinformatic analysis.

Binding of the small-molecule inhibitor CGI1746 to Bruton's tyrosine kinase (Btk), a therapeutic target for rheumatoid arthritis, induces an inactive Btk conformation. Application of this specific chemical probe reveals two Btk signaling pathways involved in inflammatory arthritis.

In addition to its incorporation into proteins, phenylalanine serves as an important precursor for natural products and components of the plant cell wall. The identification of the last gene in phenylalanine biosynthesis explains why flux in this pathway traffics through an arogenate intermediate in plants.

PKA initiates and modulates the frequency of oscillations of Ca²⁺ and cAMP in insulin-secreting cells and itself oscillates to provide spatiotemporal control of downstream signals on the basis of diverse inputs.

Cardiac glycosides, which target the Na⁺–K⁺–ATPase, block IFNβ expression by increasing intracellular Na⁺ levels to inhibit the ATPase activity of the RNA sensor RIG-I, affecting the signaling cascade downstream.

Fluorescent high-affinity activity-based probes used to monitor the activity and presence of active glucocerebrosidase in vitro and in vivo help in understanding Gaucher disease and its treatment with pharmacological chaperones.

Expression of a Huntington's-disease variant of huntingtin protein causes accumulation of the chaperone protein disulfide isomerase. This protein is the target of compounds obtained from screening for those that can alleviate cell death promoted by the mutant huntingtin, and represents a new connection between protein misfolding and cell death.

Free-energy molecular dynamics simulations and high-resolution structural analysis of the c-ring of the F₁F_o ATPase rotary motor, which mediates ion translocation, suggest conformational flexibility and reversible ion binding in the c-subunits, in an environment mimicking the a-subunit.

The antiviral S-acyl-2-mercaptobenzamide thioester ejects an essential coordinated zinc ion from and induces aggregation and dysfunction of the HIV-1 nucleocapsid protein NCp7 via repetitive intracellular enzymatic acyl transfers, dependent on acetyl-CoA.

Protein chaperones help misfolded proteins reach their native state, but the necessarily unstable substrates have complicated the analysis of chaperone function. A stable misfolded luciferase substrate now allows the determination of traditional enzyme parameters for the DnaK system, demonstrating that five cycles of unfolding and release are needed for one successful refolding event.

The ability of constrained mutants of the estrogen receptor ligand-binding domain to dictate different conformations of bound partial agonists indicates that the ability of compounds to stabilize each state determines the degree of agonist activity.

A Xenopus laevis two-reporter screen identifies the antihelminthic drug pyrvinium as an inhibitor of the Wnt/β-catenin signaling pathway that works by activating CK1α, which is likely working at the level of Pygopus, a core transcriptional component of the Wnt pathway.

Structural analysis of protein kinase A had previously focused on static pictures with bound inhibitors. The first analyses of the protein with a substrate peptide identify dynamic hot spots and slow steps in catalysis, pointing toward a model of conformational selection in binding.