News & Views in 2006

Tus proteins bound to multiple ter sequences on DNA determine the site of DNA replication termination in Escherichia coli. Biochemical and structural studies reveal how the Tus–ter complex arrests replication forks in a direction-sensitive manner.

Genetic manipulation of biosynthetic pathways is a useful method for producing analogs of complex bioactive metabolites, but this technique can be challenging when performed in the natural producer of the target compounds. Reconstruction of biosynthetic gene clusters in E. coli could be the key to rapid heterologous production of natural products and genetic manipulation of their biosynthetic pathways.

Enzymatic conversion of sphingomyelin to ceramide-1-phosphate in the external leaflet of the cellular membrane has now been shown to markedly facilitate opening of classical voltage-activated potassium channels. This discovery raises the possibility that lipids may have more prominent roles in the gating mechanism of these important ion channels than was previously appreciated.

Specialized transmembrane proteins known as G protein–coupled receptors (GPCRs) serve as universal cell surface switches to transmit hormones, neurotransmitter and other extracellular chemical signals into cells. Testing ligands of different efficacies reveals two independent modes of receptor switching.

Though uptake of beneficial foreign DNA confers fitness advantages to bacteria, the mechanisms protecting bacteria from harmful foreign DNA have been unclear. A new study suggests that the H-NS protein transcriptionally silences invading DNA by recognizing its low G-C content, thereby protecting cell viability during bacterial evolution.

Sphingosine 1-phosphate (S1P), a lysophospholipid and known immune regulator, stimulates distinct signaling pathways. A specific S1P antagonist that can be used systemically for the first time provides an indispensable tool for elucidating the therapeutic potential of the S1P signaling pathway.

Nitric oxide (NO) regulates a broad range of biological processes, yet many intracellular details of NO-mediated processes remain hidden. A new fluorescein derivative capable of direct detection provides a key advance in determining NO function in vivo.

DNA-binding proteins accomplish the remarkable feat of finding their correct target sequences within a sea of genomic DNA. A new study uses NMR spectroscopy to show the mechanism by which proteins may hop between and slide along DNA as they search for their target binding sites.

Dynamin is a large GTPase that participates in the severing of membrane-bound vesicles. A small-molecule inhibitor specific for the dynamin family of GTPases has been identified and reveals new aspects of membrane dynamics.

Nitrosoperoxycarbonate anion, a reactive species generated in inflammation processes, is able to specifically oxidize guanine bases with a sequence selectivity that is almost opposite from that usually observed for one-electron oxidants.

Copper is a requisite cofactor in myriad cellular enzymes and is shuttled to different cellular sites for the assembly of copper-containing enzymes by Cu(I)-binding metallochaperones. NMR structural studies now reveal a key step in copper ion trafficking to sites of use.

One-bead-one-compound combinatorial peptidomimetic libraries, in conjunction with a high-stringency screening method, are a powerful tool for screening peptide and peptidomimetic ligands for target proteins. Picomolar-affinity peptidomimetics for the integrin α₄β₁ have now been developed and have been successfully used to image α₄β₁-expressing tumors in living mice.

Identifying the structures of transient intermediates is an essential step in the elucidation of an enzymatic reaction mechanism. Cryocrystallography reveals the structures of three thiamine diphosphate derivatives as intermediates in the action of pyruvate oxidase.

Because of their transmembrane nature, ion channels are notoriously difficult subjects for high-throughput screening approaches. A new method has been developed that provides a simple, elegant and rapid means for assaying channel function.

When introduced into living cells, drugs frequently evoke unanticipated responses that are due either to off-target effects or to previously unknown interactions between the intended target and other biochemical pathways. The development of a panel of high-resolution sentinel assays for signal-transduction cascades in human cells promises to enhance the power of chemical genetics and increase the efficiency of drug-discovery research.

In diseases linked to protein aggregation, the initiation of aggregation can be a critical point in the disease mechanism. New studies in cells expressing huntingtin exon I suggest that the initiation of polyglutamine aggregation proceeds by a simple nucleation mechanism.