Articles in 2010

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.

The nonreceptor tyrosine kinase Btk has emerged as a new molecular target for the treatment of B cell lymphoma and autoimmune disorders. A newly discovered specific small-molecule Btk inhibitor that uniquely stabilizes Btk in an inactive conformation suppresses inflammation in rheumatoid arthritis.

Structures of 'on' and 'off' states of Crk reveal how prolyl cis-trans isomerization functions as a molecular switch in this key adaptor protein. Additionally, these structures show how an SH3 domain utilizes a noncanonical binding surface for self-regulation.

Earnest revisions based on editorial and referee feedback improve published papers.

To find out which metabolites bind to which proteins, one does not need to start with a hypothesis: it is now easiest just to do the experiments. As it turns out, some metabolites are quite promiscuous, at least in yeast.

Autophagy has emerged as a drug target for various diseases including cancer and neurodegeneration. Small molecules that affect components of the autophagic machinery and signaling pathways have led to new insights into autophagic mechanisms and also serve as lead compounds for therapeutic application.

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.

Conjugation of a known, mechanism-based glycosidase inhibitor to sensitive fluorophores yielded unexpectedly potent and selective probes for quantifying active lysosomal glucocerebrosidase. These conjugates could prove to be invaluable tools for diagnosing and studying Gaucher disease.

Although members of the Hsp70-DnaK family of heat shock proteins are involved in nearly all aspects of cell physiology, some mechanistic details of their mode of action remain obscure. A new substrate helps establish DnaK as an unfoldase that requires as little as five ATP molecules to drive the refolding of one protein.