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Coupling ligand structure to specific conformational switches in the β2 adrenoceptor. Yao et al. (p 417) showed that activation of the G protein-coupled receptor β2-AR is accompanied by at least two distinct molecular switches. The 'ionic lock' that holds together two of the transmembrane domains (red and blue) is broken upon receptor activation. Both the ionic lock switch and a 'rotamer toggle switch', which modulates helix conformation around a conserved proline kink, are required for full receptor activation (see also News & Views by Vilardaga, p 395). The authors examined the effect of agonist structure on activation of these molecular switches. Cover art by Erin Boyle based on imagery of β2-AR and small-molecule agonists provided by Charles Parnot and Xavier Deupi.
Chemical biology is an interdisciplinary field that is undergoing rapid expansion around the globe. Recently, the Japanese Society for Chemical Biology sponsored its inaugural scientific meeting to discuss research at the interface of chemistry and biology.
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.
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.
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.
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.
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.