Volume 13 Issue 6, June 2017

To fully leverage the potential of human-induced pluripotent stem cells (hiPSCs), improved and standardized reprogramming methods and large-scale collections of hiPSC lines are needed, and the stem cell community must embrace chemical biology methodology for target identification and validation.

Cell-to-cell signaling networks, although poorly understood, guide tissue development, regulate tissue function and may become dysregulated in disease. Chemical biologists can develop the next generation of tools to untangle these complex and dynamic networks of interacting cells.

Notch signaling is an essential cell–cell communication pathway that influences numerous cell fate decisions during development. Structural and biochemical studies of a Notch–Jagged complex dramatically advance current understanding of ligand recognition, and reveal evidence of catch-bond behavior in the complex.

Biologic drugs that modulate the immune system have revolutionized the therapeutic landscape for several selected cancer types. A new study reports an image-based assay system to monitor cell–cell interactions, identifying small-molecule compounds with immunomodulatory capacity.

Multiple optogenetic technologies are required to control biological activity simultaneously with different colors of light. Optimizing a near-infrared-induced heterodimerization system, which can be combined with blue-light-controlled domains, enables precise spatiotemporal control of target molecules in live mammalian cells.

Chemical control of protein homeostasis and induction of protein destabilization are emerging therapeutic strategies. Two recent studies identify a set of sulfonamides that can modulate the CRL4^DCAF15 E3 ligase complex to target the splicing factor RBM39 for proteasomal degradation.

Most microbial biosynthetic gene clusters are inactive under laboratory culture conditions. A CRISPR–Cas9 genome-editing approach in Streptomyces species enables the targeted activation of silent gene clusters and production of encoded natural products.

Crystal structures of human O-GlcNAc hydrolase (hOGA) fragments show that hOGA's dimeric structure is organized by swapping of an α-helical element and reveal features of inhibitor binding to the catalytic domain.

Crystallographic analysis of human O-GlcNAc hydrolase (hOGA) fragments containing the catalytic domain, including structures in complex with known inhibitors, suggests that OGA is functional as a dimer and defines opportunities for structure-based drug design.

Ataxia telangiectasia mutated (ATM) directly interacts with and phosphorylates the V-ATPase V₁ subunit ATP6V1G1, thereby decreasing V₁-V₀ assembly in the V-ATPase. Attenuation of ATM activity results in lysosomal pH acidification, recovery of autophagy and alleviation of senescence.

The generation of low-molecular-weight protein tyrosine phosphatase (LMPTP) knockout mice combined with the identification of a small-molecule uncompetitive LMPTP inhibitor reveals a role for LMPTP in regulating insulin resistance.

The engineering of Q-PAS1, a single-domain variant of PpsR2, led to an optimized optogenetic system based on the Q-PAS1–BphP1 interaction, which was applied to the regulation of transcription, epigenetic state and protein localization by near-infrared light.

Characterization of an enterohaemorrhagic E. coli toxin–antitoxin system reveals that the toxin AtaT specifically acetylates Met-tRNA^fMet at the methionyl amine, making it incompetent for translation initiation, which inhibits translation.

mmPEGC-C22 is a nonsterol glycolipid involved in early Caenorhabditis elegans larval development that can rescue the growth-arrest phenotype caused by sterol deficiency and is controlled by TGF-β to help mobilize internal sterol pools.

Structural analysis and spectroscopy elucidate how pairs of electrons are bifurcated in a flavoenzyme by generating an unstable flavin semiquinone, thus coupling exergonic and endergonic oxidation–reduction reactions.

Structures of pimeloyl-CoA synthetase (BioW) provide insights into its catalytic mechanism and how it selects the correct length of dicarboxylic acid substrate, guiding engineering to make the enzyme capable of producing alternative CoA products.

Structural analysis of pimeloyl-CoA synthetase (BioW) provides insight into how the enzyme ensures proper substrate positioning and how a key residue ensures proofreading of the reaction through hydrolysis of noncognate adenylated substrates.

A series of sulfonamides induced the ubiquitin-mediated degradation of the U2AF-related splicing factor, coactivator of activating protein-1 and estrogen receptor α (CAPERα), by promoting direct binding between CAPERα and the CRL4 substrate receptor DCAF15.

A high-content screening platform that measures the immunological potential of small-molecule and biologic drugs by computationally determining changes in the physical interactions among peripheral mononuclear leukocytes revealed known immunomodulators and also approved drugs as regulators of unexpected targets, including MST1R.