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  • We used chemical proteomics to identify candidate protein targets of indole metabolites in mammalian cells. We discovered that microbiota-derived and synthetic aromatic monoamines can activate recruitment of β-arrestin to the orphan receptor GPRC5A. Specific microbiota species that express amino acid decarboxylases were found to produce aromatic monoamine agonists for GPRC5A.

    Research Briefing
  • A new platform for screening nucleophilic-fragment-based covalent ligands enables the identification and targeting of ligandable sulfenic acid sites, setting the stage for exploration of nucleophile-directed probe and drug development.

    • Daniel W. Bak
    News & Views
  • Systematically culturing combinations of auxotrophic yeast mutants leads to the identification of pairs that form obligatory cross-feeding relationships, some of which are stable over time and can divide metabolic labor for biotechnological applications.

    • Simran Kaur Aulakh
    • Lara Sellés Vidal
    • Rodrigo Ledesma-Amaro
    ArticleOpen Access
  • Chemoproteomics reveals a vast expanse of ligandable cysteine sulfenic acids in the human proteome, highlighting the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline.

    • Ling Fu
    • Youngeun Jung
    • Kate S. Carroll
  • Lowering the levels of disease-promoting proteins is generally assumed to be beneficial. The authors developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic locus. This approach was used to study the effect of BACH1 levels on MDA-MB-231 human breast metastatic cells.

    • Yiming Wan
    • Joseph Cohen
    • Gábor Balázsi
    ArticleOpen Access
  • Protein stability is important for biological function, but little is known about in-cell stability. In the New Delhi metallo-β-lactamase NDM-1, enhancement of zinc binding or amino acid substitutions at the C terminus increase in-cell kinetic stability and prevent proteolysis. These findings link NDM-1-mediated resistance with its in-cell stability and physiology.

    Research Briefing
  • The medicinal plant Catharanthus roseus is a source of leading anticancer drugs. The monoterpene indole alkaloid (MIA) biosynthetic pathway in C. roseus has now been analyzed using a complementary, multi-omics, single-cell approach. This identified clusters of genes involved in MIA biosynthesis and cell-type-specific partitioning in the MIA biosynthetic pathway.

    • Chenxin Li
    • Joshua C. Wood
    • C. Robin Buell
    ArticleOpen Access
  • Itskanov and Wang et al. determined high-resolution structures of the human Sec61 channel inhibited by several structurally distinct small molecules and revealed the common inhibitor-binding site in Sec61 and molecular interactions in atomic detail.

    • Samuel Itskanov
    • Laurie Wang
    • Eunyong Park
  • A selective inhibitor of Sec61 blocks protein entry into the secretory pathway and has therapeutic efficacy in rheumatoid arthritis. A cryo-EM structure of the inhibited Sec61 provides a model for client-selective protein translocation inhibition.

    • Shahid Rehan
    • Dale Tranter
    • Ville O. Paavilainen
    ArticleOpen Access
  • Tricyclic peptides have reduced conformational flexibility, making them well suited for ligand development. Researchers have now generated large combinatorial libraries of tricyclic peptides using a disulfide-directing motif. Screening these libraries discovered binders to challenging protein targets.

    • Christian Heinis
    News & Views
  • The bacterium Proteus mirabilis natively forms a bullseye colony pattern by swarming. Doshi et al. engineered this bacterium to encode environmental inputs, including copper, into its pattern features, and decoded them with image processing and deep learning.

    • Anjali Doshi
    • Marian Shaw
    • Tal Danino