Chemical genetics

  • Article
    | Open Access

    Citrullination of arginine is crucial for several physiological processes. Here the authors report the site-specific incorporation of citrulline into proteins in mammalian cells using an engineered tRNA synthetase/tRNA pair and a photocaged-citrulline.

    • Santanu Mondal
    • , Shu Wang
    •  & Paul R. Thompson
  • Article
    | Open Access

    Identifying chemical-genetic interactions in mammalian cells is limited to low-throughput or computational methods. Here, the authors present QMAP-Seq, a broadly accessible and scalable approach that uses NGS for pooled high-throughput chemical-genetic profiling in mammalian cells.

    • Sonia Brockway
    • , Geng Wang
    •  & Marc L. Mendillo
  • Article
    | Open Access

    Artemisinin (ART) resistance poses a problem for malaria elimination. Here, the authors perform genome-wide CRISPR screens in Toxoplasma gondii and identify that the putative transporter Tmem14c and mitochondrial heme metabolism, through mitochondrial protease DegP2, affect ART susceptibility.

    • Clare R. Harding
    • , Saima M. Sidik
    •  & Sebastian Lourido
  • Article
    | Open Access

    Chemical tools to monitor drug-target engagement of endogenous enzymes are essential for preclinical target validation. Here, the authors present a chemical genetics strategy to study target engagement of endogenous kinases, achieving specific labeling and inactivation of FES kinase to provide insights into FES’ role in neutrophil phagocytosis.

    • Tom van der Wel
    • , Riet Hilhorst
    •  & Mario van der Stelt
  • Article
    | Open Access

    The genetics underlying bacterial susceptibility to antimicrobial peptides (AMPs) remain unclear. Here, using a genome-wide chemical-genetic approach, the authors map the diversity of resistance determinants across AMPs in Escherichia coli and provide evidence that cross-resistance is prevalent only between AMPs with similar modes of action.

    • Bálint Kintses
    • , Pramod K. Jangir
    •  & Balázs Papp
  • Article
    | Open Access

    Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish.

    • Matthew N. McCarroll
    • , Leo Gendelev
    •  & David Kokel
  • Article
    | Open Access

    Core regulatory transcription factors are usually regulated by cell-type specific super enhancers (SEs). Here, the authors screen for chemical probes able to distinguish between SE-driven and promoter-driven transcription and find that histone deacetylases are selectively required for core regulatory transcription.

    • Berkley E. Gryder
    • , Lei Wu
    •  & Javed Khan
  • Article
    | Open Access

    Premature termination codon suppression therapy could be used to treat a range of genetic disorders. Here the authors present a high-throughput cell-based assay to identify anticodon engineered tRNAs with high suppression activity.

    • John D. Lueck
    • , Jae Seok Yoon
    •  & Christopher A. Ahern
  • Article
    | Open Access

    Designing split protein approaches is time consuming and often results in high background activity due to spontaneous assembly. Here the authors present an automated approach which uses a split energy scoring function to identify optimal protein split sites and reduces spontaneous assembly.

    • Onur Dagliyan
    • , Andrey Krokhotin
    •  & Nikolay V. Dokholyan
  • Article
    | Open Access

    Engineering E. coli for metabolization of methanol to produce fuels and chemicals has not been fully achieved. Here, the authors combine metabolic engineering and chemical inhibition to improve methanol assimilation and distinguish the role of kinetics and thermodynamics under various culture conditions.

    • Benjamin M. Woolston
    • , Jason R. King
    •  & Gregory Stephanopoulos
  • Article
    | Open Access

    The bidirectional Eph-ephrin signalling regulates a myriad of developmental programmes. Zhang et al. show that EphB4 forward signalling is crucial for lymphatic valve development, providing new insight into this important developmental process previously thought to be regulated by ephrinB2-dependent reverse signalling.

    • Gu Zhang
    • , John Brady
    •  & Minhong Yan
  • Article
    | Open Access

    Focal epilepsy is difficult to treat with currently available drugs or surgical approaches. Kätzel et al.express mutant inhibitory receptors in the brains of rats with focal epilepsy and selectively activate these receptors by an exogenous compound, which results in region- and time-specific suppression of focal seizures

    • Dennis Kätzel
    • , Elizabeth Nicholson
    •  & Dimitri M. Kullmann