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Recent crystal structures of a bacterial copper tolerance protein reveal an intriguing copper binding site that includes tryptophan. Its close proximity coupled with spectroscopic data suggests an unusual cation-π interaction between Cu(I) and the aromatic ring of tryptophan.
Schizophrenia is thought to involve a dysfunction of glutamatergic and GABAergic signaling in the prefrontal cortex, but how these systems interact in the disease has been unclear. Now ketamine, a glutamatergic NMDA receptor antagonist, may provide a mechanism that could link these pathways.
The MRN protein megacomplex mediates repair of double-stranded DNA breaks (DSBs) by tethering together broken ends of chromosomes and signaling a cascade of events required for DNA repair. The first small-molecule inhibitor that disrupts MRN function provides a valuable new tool for functional studies of DSB repair in cells.
Myristoylation is an important post-translational modification that targets many signaling proteins to membranes. Now the crystal structure of calcium-bound myristoylated GCAP-1 demonstrates a new structural role for protein myristoylation.
Extending the time animals spend in the vigorous phase of their lives would have enormous economical and social consequences. A new study reveals that antidepressants commonly used in humans can significantly prolong the life of nematodes by antagonizing conserved G protein–coupled receptors.
Charge pairing between neighboring amphotericin B molecules inserted into the membrane is believed to significantly stabilize supramolecular channel architecture. Now the synthetic “knockout” of a carboxylic acid in amphotericin B, generated in an exacting ten-step chemical sequence, shows this interaction is not required for function.
Analyses of mutants affecting the synthesis of inositol phosphates have uncovered a variety of new roles for these small molecules in cells, but identification of their physiological targets has lagged behind. New studies on the yeast phosphate starvation response have brought the inositol pyrophosphate IP7 and its mechanism of action into sharp focus.
The combination of high-content small-molecule screening information with computational tools offers the opportunity to obtain structure-activity relationships from complex cell-based data.
Analysis of the multifunctional bone morphogenetic protein (BMP) signaling pathway has been hampered by the lack of specific reagents for discriminating downstream signaling events. A new study uses a novel zebrafish embryo screen to identify dorsomorphin, the first small-molecule inhibitor of BMP signaling, and shows its application in fields as diverse as osteogenesis, developmental patterning and iron homeostasis.
Though the chemical mechanisms of many enzymes have been elucidated, the mechanisms by which specificity and rate acceleration are achieved remain less explored. A new study suggests that physically controlled processes, such as active site access and organization, are rate limiting for enzymatic catalysis.
How do drugs work? What molecular changes do they cause in cells and in organisms? Is there a paradigm shift in the way we can predict and appreciate the impact of small molecules on biological systems in the 21st century? These were some of the questions addressed at a meeting in Vienna in August 2007.
