News & Views

  • News & Views |

    Phenotypic screening is an engine of discovery for bioactive small molecules and can unravel novel mechanisms and pathways controlling cellular physiology. A recent study reveals the CPSF complex as a pharmacologically tractable target of JTE-607 and context-specific cancer dependency.

    • Michael A. Erb
  • News & Views |

    Molecular-glue-mediated proximity-induced degradation now allows unprecedented therapeutic targeting of previously undruggable proteins. Structures showing how aryl-sulfonamides mediate recruitment of the splicing factor RBM39 to the E3 CRL4DCAF15 broaden the mechanistic principles by which molecular glues target ubiquitylation.

    • Kheewoong Baek
    •  & Brenda A. Schulman
  • News & Views |

    Actin cytoskeletal structures are essential for many cellular processes, and cofilin is a key protein for the assembly of these highly dynamic structures. A new cofilin construct enables precise optogenetic control of actin assembly in live cells.

    • Qian Chen
  • News & Views |

    The last step of archaeosine biosynthesis was found to involve two enzymes, the previously known ArcS with lysine transfer activity and a novel identified radical SAM enzyme named RaSEA.

    • Mohamed Atta
  • News & Views |

    The regulation of brain iron homeostasis, previously thought to be cell autonomous and modulated by local factors in the interstitial fluid, is reported by Wang et al. to be strongly influenced by axonal transport of iron in an activity-dependent and unidirectional manner between functionally associated regions. The supply of iron from the ventral hippocampus to the middle prefrontal cortex subserved an anxiolytic phenotype and mediated the neuropharmacological actions of diazepam and lithium chloride in rodent models.

    • Peng Lei
    • , Scott Ayton
    •  & Ashley I. Bush
  • News & Views |

    The growth and guidance of axons dictate their trajectories and are critical for neural-circuit formation. Research in this issue uncovers a new mechanism for regulation of axon growth and guidance that acts via extracellular phosphorylation of a receptor.

    • Patricia T. Yam
    •  & Frederic Charron
  • News & Views |

    Riboswitches enable microbes to rapidly respond to changing levels of metabolites. A high-throughput platform reveals how RNA structural transitions kinetically compete during transcription in a new mechanism for riboswitch function.

    • Margaret L. Rodgers
    • , Yumeng Hao
    •  & Sarah A. Woodson
  • News & Views |

    Cytoplasmic dynein is a complex molecular motor that steps along microtubules. Advanced biophysical measurements reveal a surprising role for the dynein tail domain in the allosteric control of dynein’s mechanochemistry within assemblies composed of multiple dynein motors.

    • Richard J. McKenney
  • News & Views |

    A comprehensive genetic screen reveals new cellular trafficking factors and linker-dependent requirements for antibody–drug conjugate (ADC) cytotoxicity. These new insights may guide the design of optimized ADCs.

    • Heather A. Van Epps
    •  & Peter D. Senter
  • News & Views |

    An unusual terpene nucleoside, 1-TbAd, made by pathogenic mycobacteria acts as an antacid to block mycobacterial degradation in host cell vacuoles. The antacid activity acts to reduce acidity by neutralizing the pH of these degradative cell organelles.

    • Priscille Brodin
    •  & Eik Hoffmann
  • News & Views |

    Asymmetric cell division, which generates daughter cells with distinct characteristics, is a mechanism for creating complex systems through cellular differentiation. Two studies in this issue develop synthetic platforms that program spatial localization of genetic material or signaling molecules to enable asymmetric cell division in Escherichia coli.

    • Helena R. Ma
    •  & Lingchong You
  • News & Views |

    A new sugar-based cysteine-reactive probe, combined with competitive activity-based protein profiling (ABPP), enables site-centric target deconvolution of itaconate in native proteomes, shedding light on a novel mechanism of action for this important immunoregulatory metabolite in inflammatory macrophages.

    • Jing Yang
  • News & Views |

    The N6-methyladenosine modification on RNA affects almost all steps of RNA metabolism. A new approach, using the CRISPR-based technology to modulate m6A level in mRNA, enables direct functional interrogation of site-specific m6A.

    • Jiangbo Wei
    •  & Chuan He
  • News & Views |

    Using knowledge of their evolutionary origin, an automated platform has been developed to provide accurate de novo structural predictions of products from trans-acyltransferase polyketide synthases.

    • Matthew Jenner
  • News & Views |

    A new small molecule that targets the vacuolar H+-ATPase activates autophagy, inhibits mTORC1 signaling, and displays potential for clearing toxic protein aggregates involved in neurodegenerative diseases.

    • Delong Meng
    •  & Jenna L. Jewell
  • News & Views |

    Autophagy is a ‘self-eating’ recycling process that maintains cellular homeostasis. Autogramins were identified as small-molecule autophagy inhibitors that target the cholesterol transport protein GRAMD1A, revealing a role for cholesterol in autophagosome biogenesis.

    • Leslie N. Aldrich
  • News & Views |

    The limited availability of small-molecule ligands for E3 ubiquitin ligases stymies the development of next-generation degraders. Two recent papers report the identification of novel, covalent and PROTAC-compatible ligands that hijack the previously untargeted ligases RNF114 and DCAF16.

    • Matthias Brand
    •  & Georg E. Winter
  • News & Views |

    The advent of PROTACs that degrade the entire protein target rather than simply inhibiting it bring druggable yet apparently non-functional binding sites into play for medicinal chemists to do their work.

    • Dafydd Owen
  • News & Views |

    The NLRP3 inflammasome contributes to pathogenic inflammation in a broad range of diseases, making it a highly relevant drug target. Two studies published in this issue found an inhibitor of NLRP3 inflammasome activation to directly bind NLRP3 within its central NACHT domain, interfering with ATP hydrolysis and structural changes critical for NLRP3 oligomerization and subsequent inflammasome formation.

    • Oliver Gorka
    • , Emilia Neuwirt
    •  & Olaf Groß
  • News & Views |

    Endocytosis mediates the internalization of proteins and lipids at the plasma membrane and plays essential roles in plant growth and development. A new small molecule enables manipulation of plant endocytosis in an acute and transient manner.

    • Chunhua Zhang
    •  & Glenn R. Hicks
  • News & Views |

    Chemical probes that irreversibly inhibit protein function may be used across species to discover proteins. Combining phenotypic screening and activity-based protein profiling, a new study uncovers a discrete lipid signaling pathway regulating lifespan in the worm Caenorhabditis elegans.

    • Jürg Gertsch
  • News & Views |

    Arginine protein kinases regulate bacterial signaling cascades through phosphorylation of key arginine residues. Crystal structures of the kinase McsB provide the first glimpse of how these unusual enzymes recognize their protein substrates and are allosterically regulated.

    • Titus J. Boggon
  • News & Views |

    The molybdenum cofactor (Moco) is a fragile prosthetic group essential for most organisms. Nematodes are now capable of extracting Moco from their bacterial diet to mediate detoxification of sulfite.

    • Ralf R. Mendel
    •  & Thomas W. Hercher
  • News & Views |

    The N6-methyladenosine modification next to the 5′ RNA cap has dynamic regulatory functions. Recent findings show that this modification regulates the splicing and translational activity of different classes of RNAs.

    • Richard A. Padgett
  • News & Views |

    Powerful combinatorial peptide library methods allow the discovery of peptide leads from diverse libraries. A new platform based on tandem mass spectrometry peptide sequencing coupled with high-performance size-exclusion chromatography enables identification of high-affinity peptidic ligands from focused libraries.

    • Kit S. Lam
  • News & Views |

    Potassium channels allow the passage of potassium ions across membranes at rates approaching the diffusion limit while maintaining exquisite selectivity between ion species. Single-molecule studies now reveal that the selectivity filter of these proteins transitions between different conformations.

    • Adrian Gross
  • News & Views |

    A small molecule was identified that binds to a unique site on the pro-apoptotic protein BAX, stabilizing the protein structure allosterically and preventing the conformational activation to a pore former by BH3 proteins.

    • Jialing Lin
  • News & Views |

    A new method introduces ubiquitin or ubiquitin-like proteins at specific sites in any protein without the requirement of the cellular ubiquitylation machinery. This will help decipher the code by which these modifications control cellular processes.

    • Amit Kumar Singh Gautam
    •  & Andreas Matouschek
  • News & Views |

    Cell envelope assembly during V snapping, an unusual method of cell division in Actinobacteria, is mechanistically different than that seen during cell division of many other bacteria.

    • Martin S. Pavelka Jr.
  • News & Views |

    Holliday junction resolvases lock dynamic DNA four-way junctions into specific structural conformations for symmetric DNA cleavage. Single-molecule studies now reveal that resolvases can relax their grip, enabling Holliday junction conformer transitions and branch migration in the enzyme-bound form.

    • Ulrich Rass
  • News & Views |

    Faster-than-transcription control of cellular activities is an important but challenging engineering target. Using split ferredoxins and induced dimerization or conformational changes, newly developed metalloprotein switches provide a fast method to control electron flux.

    • Michaela TerAvest
  • News & Views |

    Two protein circuit systems, split-protease-cleavable orthogonal coiled-coil logic (SPOC logic) and circuits of hacked orthogonal modular proteases (CHOMP), have been developed to permit rapid and logic function-based control of mammalian cellular signaling.

    • Yiqian Wu
    •  & Yingxiao Wang
  • News & Views |

    The carboxyl-terminal domain (CTD) of RNA polymerase II (Pol II) is post-translationally modified during gene expression. A recent study has identified a CTD kinase, Hrr25, that regulates the termination of noncoding RNA genes by recruiting Rtt103, a key termination factor.

    • Carlos Mario Genes Robles
    •  & Frédéric Coin
  • News & Views |

    Characterization of a novel mutation in the E2 ubiquitin-conjugating enzyme UBE2A accounts for the decreased activity of the mutant enzyme that underlies disease and provides important insight into the catalytic mechanism of E2s.

    • Martina Foglizzo
    •  & Catherine L. Day
  • News & Views |

    Phase separation underlies the formation of cellular membrane-less organelles. A new report identifies deacetylation at lysine residues of intrinsically disordered protein regions to drive liquid droplet formation in vitro and stress granule maturation inside cells.

    • Alessia Ruggieri
    •  & Georg Stoecklin
  • News & Views |

    Prostanoids signal through G-protein-coupled receptors to regulate diverse physiological processes. Structures of three prostanoid receptors in inactive and active conformations now uncover the molecular determinants of ligand recognition and receptor activation and offer new opportunities for drug discovery.

    • Kaspar Hollenstein
  • News & Views |

    Terpenoids are assembled from five-carbon (C5) units, which limits the available scaffold chemical space for the discovery of bioactive molecules. A combination of enzyme and metabolic engineering now enables biosynthesis of a plethora of non-natural C11 terpenoids.

    • Yongjin J. Zhou
  • News & Views |

    Scientists have combined functional and computational analysis to predict the substrate specificity of a family of glycosyltransferases from Arabidopsis thaliana, creating a tool that enables researchers to classify the donor and acceptor specificity of glycosyltransferase enzymes.

    • Jochen Schmid
  • News & Views |

    The proteome-wide application of a probe that selectively labels cysteine residues oxidized to the sulfinic acid form reveals the mammalian S-sulfinylome and uncovers novel substrates of the sulfinyl reductase sulfiredoxin, opening yet unexplored realms of cysteine-based redox regulation.

    • Sophie Rahuel-Clermont
    •  & Michel B. Toledano
  • News & Views |

    A Donnan equilibrium causes an influx of chloride ions into the Escherichia coli periplasm when the bacterium finds itself in gastric fluid. The combination of low pH and high anion concentration drives proteins to aggregate, a potentially lethal event unless prevented by specific chaperones.

    • Colin Kleanthous
  • News & Views |

    Current drug discovery efforts focus on proteins because of their ability to form stable, structured pockets. A recent study demonstrates that targeting stable, structured bioactive RNA motifs, such as autocatalytic introns, may provide a novel method of expanding druggability and selectivity.

    • James Palacino
  • News & Views |

    The prodrug dimethyloxalylglycine (DMOG) is a well-known tool compound used to study hypoxia. New findings reveal that DMOG also inhibits glutamine metabolism and can be exploited to selectively kill some cancer cells, highlighting important caveats when using DMOG for hypoxia studies.

    • Barbara S. Nelson
    • , Daniel M. Kremer
    •  & Costas A. Lyssiotis
  • News & Views |

    Duramycin is a small post-translationally modified peptide with antibody-like affinity for phosphatidylethanolamine. As it turns out, the same functionality that is essential for duramycin activity helps to catalyze the formation of its conformationally constrained and compact polycyclic architecture.

    • Albert A. Bowers
  • News & Views |

    T cell cross-reactivity enables the immune system to recognize a large array of peptides. A new study shows that T cells can achieve cross-recognition by using the remarkable plasticity of peptides, through flipping the peptide out of the binding cleft.

    • Stephanie Gras
  • News & Views |

    One mechanism of thalidomide teratogenicity involves binding to the CUL4–CRBN E3 ubiquitin ligase complex, which then mediates the degradation of transcription factors. New studies reveal that species-specific variants of the transcription factor SALL4 are differentially ubiquitinated and degraded via the thalidomide-bound complex.

    • Peter G. Wells
  • News & Views |

    The design of spiraling cross-α amyloid-like structures reveals fascinating supermolecular fibrils of diverse compactness and stability. The small sequence variations governing cross-α self-assembly properties concur with amyloids being basic building blocks of life and natural targets for microbial structural mimicry.

    • Meytal Landau
  • News & Views |

    A computational design approach was used to develop a genetically encoded FRET-based optical sensor that is aimed at monitoring extracellular glycine levels in brain tissue with the sensitivity and resolution to discern differences in dendritic spine and shaft environment and concentration dynamics upon afferent stimulation.

    • Dmitri A. Rusakov
  • News & Views |

    Calcium channels are crucial regulators of a broad range of biological processes. A photoswitchable chemical probe allows the opening and closing of these channels with unprecedented temporal resolution, providing new opportunities to study calcium-dependent signaling pathways in real time.

    • Marc Vendrell
  • News & Views |

    Monitoring MHC-I dynamics upon binding to its chaperone TAPBPR helps us understand how optimal peptide sequences are selected for presentation and coordinated with release of the chaperone from the ternary peptide–MHC-I–TAPBPR complex.

    • Tim Elliott
  • News & Views |

    Establishment of the germ cell lineage requires post-transcriptional regulation of mRNAs, yet the underlying molecular mechanisms are not fully understood in vertebrates. A small-molecule inhibitor of germ cell formation reveals a noncanonical translation system used in zebrafish embryos.

    • Yuichiro Mishima