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The report of a new class of potent and highly selective inhibitors of Bcr-abl highlights the potential for a truly leukemia-specific drug with no expected off-target activity. GNF-2, as a representative compound of this class, may have inspired the identification of a region of Bcr-abl that is amenable to drug design, just as imatinib did almost a decade ago.
Studies have linked the Fucα(1-2)Gal modification of neuronal glycoproteins to cognitive processes such as learning and memory. The identification of synapsins Ia and Ib as the main Fucα(1-2)Gal-bearing neuronal proteins not only suggests previously unknown molecular mechanisms of neuronal plasticity but also indicates the existence of previously unknown glycosylation pathways in neurons.
DNA in the nucleus of mammalian cells is extensively associated with proteins. Potential anticancer agents can access, recognize and alkylate nucleosomal DNA, even at sites that seem completely occluded by association with histone proteins.
Modern single-molecule tools, when applied to enzymes, challenge fundamental concepts of catalysis by uncovering mechanistic pathways, intermediates and heterogeneities hidden in the ensemble average. It is thus reassuring that the Michaelis-Menten formalism, a pillar of enzymology, is upheld, if reinterpreted, even when visualizing single turnover events with a microscope focus.
A small-molecule inhibitor of protein secretion has been found that targets Cdc42, a regulator of the secretory pathway. This compound acts through a previously undescribed mechanism—by recruiting a protein inhibitor.
Ion channels have essential roles in the nervous system. An engineered ligand-gated channel with a photoactivated switch will be useful for addressing several issues in neuronal signaling.
Neurotransmitter binding to a member of the Cys-loop receptor superfamily elicits opening of an ion channel by inducing a change in the configuration of a prolyl imide bond. Engineering a series of mutant receptors to contain proline analogues with a range of cis/trans preferences demonstrates the molecular basis for channel gating.
Methylation is a key regulatory event in several biological processes. The enzymatic transfer by methyltransferases of extended carbon chain analogs of S-adenosylmethionine to DNA opens up new avenues for investigating biological methylation.
Hedgehog signaling has important and pleiotropic roles in embryonic and adult tissues. A small-molecule agonist of this pathway has been shown to act by targeting the transmembrane protein Smoothened.
