Articles in 2010

Determining relevant targets of promiscuous kinase inhibitors has proven difficult. A combination of two mass spectrometry–based proteomic approaches, RNAi depletion and rescue studies with drug-resistant mutants now reveal that SRC, FYN and EGFR are functionally important targets of dasatinib in lung cancer cells.

Ribosomal decoding is dependent on wobble base pairing, which frequently involves modified nucleotides in the tRNA anticodon loop. The discovery of a new guanidine-modified base, 2-agmatinylcytidine, in the tRNA^Ile of archaea uncovers the mechanism for AUA decoding in these organisms.

In contrast to perceived nonselectivity, biochemical profiling reveals that currently available HDAC inhibitors predominantly inhibit only class I and IIb HDAC enzymes. A new pan-selective inhibitor, obtained by screening a focused library, provides an important tool for studying class IIa HDACs.

Cycloheximide is a natural product that cell biologists have used for decades as a tool to arrest protein synthesis in eukaryotes. Biochemical data now refine our mechanistic view of how cycloheximide and structurally related analogs inhibit translational elongation.

Group II introns can act as mobile genomic elements and integrate into genomic DNA through reverse splicing. A selective nucleotide modification approach was used to show that the 2′-hydroxyl at the ribozyme 3′ terminus plays a catalytic role as a proton shuttle during reverse splicing.

The prion strain phenomenon states that distinct amyloid conformations with different phenotypes and heritable states can arise from a single polypeptide. The decision about amyloid conformation is made at the level of the initial nucleus, where different nuclei will lead to different conformations.

Despite the need for new psychoactive drugs, there are few robust approaches for discovering novel neuroactive molecules. Development of a behavior-based high-throughput screen in zebrafish led to the discovery of molecules with neurological effects. Translating the complex behavioral phenotypes elicited by compounds into a simple barcode enabled identification of their mechanism of action.

Upregulation of PI(3)K signaling pathways is implicated in many diseases, and a number of inhibitors are currently in clinical development. The structure of a PI(3)Kδ kinase domain, along with co-complexes with a diverse range of inhibitors, reveals new insights into mechanisms of inhibition and suggests isoform-selective design strategies.

Differences in packing and solvent exposure of hydrophobic residues determine the interactions with cell membranes and toxicity of different oligomers of the model protein HypF-N.