Volume 7 Issue 1, January 2011

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.

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.

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.

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.

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.

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.

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.

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.

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.