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As the final collection of articles celebrating ten years of publication of Nature Chemical Biology, this issue explores a snapshot of the countless frontiers within the field of chemical biology. Like the new stars of the Milky Way Galaxy's Arches cluster observed by the Hubble Space Telescope and ground-based telescopes and depicted on the cover, the field of chemical biology is young and ripe for expansion and exploration. Image credit: NASA, ESA and A. Schaller (for STScI).
Abundant frontiers at the interface of chemistry and biology promise another decade of technological innovation and scientific discovery by chemical biologists.
Misregulated transcription factors play prominent roles in human disease, but their dynamic protein-protein interaction network has long made the goal of transcription-targeted therapeutics impractical. Recent advances in technologies for modulating protein interaction networks mean that the end of the quest is in sight.
X-ray crystallography, the workhorse of structural biology, has been revolutionized by the advent of serial femtosecond crystallography using X-ray free electron lasers. Here, the fast pace and history of discoveries are discussed together with current challenges and the method's great potential to make new structural discoveries, such as the ability to generate molecular movies of biomolecules at work.
We asked a collection of chemical biologists: “What is the most exciting frontier area in chemical biology, and what key technology is needed to advance knowledge and applications at this frontier?”
Selecting compounds for the chemical library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many molecules in the Novartis and NIH Molecular Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compounds of interest.
25-Hydroxycholesterol induces miR-185 to suppress lipid and cholesterol synthesis pathways and inhibit viruses such as hepatitis C virus (HCV), that use host membranes to propagate. HCV counteracts this by suppressing miR-185 expression to drive increased cellular lipid content.
A new high-resolution crystal structure of the subdomain from a catalytically active group II intron reveals important conformational rearrangements necessary to achieve the fully formed catalyst. This structure provides the first atomic-resolution structure of an RNA folding intermediate.
Some polyketide synthase pathways include branching modules that insert branched monomers into polyketide products. In vitro reconstitution using swapped domains now shows that the mysterious branching (B) domain and the homologous X domain in these modules have structural rather than catalytic roles.
The combination of a light-activated receptor tyrosine kinase and a fluorescent MAPK/ERK reporter results in the development of an optogenetics-based cell screening method to identify small-molecule inhibitors of RTK signaling.
Structure and functional characterization of BpHep, a heparanase from the invasive pathogenic bacterium Burkholderia pseudomallei, defines its glycosaminoglycan recognition mechanism and its catalytic mechanism as an endo-acting glycoside hydrolase.
Unique activities and high potency at disease-relevant biological targets can now be identified for ‘dark chemical matter’—compounds in high-throughput screening libraries that have been extensively tested but that have never been annotated as having biological activity.
A crystal structure of an RNA folding intermediate of the group II intron reveals a compact conformation that is stabilized by the sequential docking of downstream intron domains, providing new insights into RNA tertiary structure assembly.
Chemoproteomic studies have revealed that a Wnt-pathway inhibitor, CCT251545, is a potent and selective small-molecule chemical probe that inhibits the Mediator complex–associated protein kinases CDK8 and CDK19 through a type 1 binding mode and modulates the growth of Wnt-dependent tumors.
Single-molecule experiments reveal the unfolding and refolding landscape of the rhomboid protease GlpG in a native-like lipid membrane. GlpG unravels cooperatively in a single step and has a large unfolding barrier, making for a long-lived folded state.
25-Hydroxycholesterol induces expression of the microRNAs miR-130b and miR-185 in HCV-infected cells, and these inhibit viral fatty acid desaturation, lipid uptake and biosynthesis, thereby limiting infection. HCV counteracts this immunometabolic response by downregulating these microRNAs.
This special issue, the last of our 10th anniversary Vol., presents a collection of articles focused on "Frontiers in chemical biology" and identifies some of the emerging scientific areas that will engage chemical biologists in the coming years.