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Research in the early days of chemical biology was mostly limited to the application of chemical tools to model cell lines grown in incubators. Now, discoveries are being made in more physiologically relevant systems, from tissues to organisms, using precisely targeted molecules. The 2023 Chemical Biology & Physiology meeting (in Portland, Oregon) discussed the latest advances in the field, with research from around the globe demonstrating that the transition to making discoveries at the chemical biology–physiology interface is happening now.
Orally bioavailable, high molecular weight macrocyclic peptides that inhibit difficult-to-drug protein–protein interactions are of high therapeutic value, and rules for their design were proposed recently. Here, we emphasize the danger of rules that provide a false impression of the lipophilicity required of a clinical candidate.
A tRNA modification, named 2-aminovaleramididine (ava2C), has been discovered in plant organelles and bacteria. Structural analysis shows specific codon recognition by this modification, highlighting the evolutionary diversity of the essential tRNA modifications.
Li, Cheng, Yu and colleagues have discovered a Cas13j family, including the compact and highly efficient LepCas13j (529 aa) and ChiCas13j (424 aa), with promising applications in RNA editing in vivo.
Development of a paralog-hopping approach leveraging chemical proteomic data on covalently liganded cysteines revealed an allosteric pocket shared by cysteine-containing and cysteine-less paralogous cyclin E proteins.
A modular multicellular system has been created by mixing and matching discrete engineered bacterial cells in an artificial neural network-type architecture. The system is capable of solving multiple computational decision problems like identifying a number as prime and a letter as a vowel.
Naturally occurring peptide–nucleobase hybrids are rare. Here Pei et al. report the discovery and biosynthetic studies of the first peptide–nucleobase hybrid catalyzed by an RRE–YcaO–dehydrogenase complex from a RiPP pathway, and show the biotransformation in a substrate-assisted manner.
The incorporation of nitrogen in steroidal glycoalkaloids is hypothesized to occur through a transamination reaction. Here, the authors show that GLYCOALKALOID METABOLISM12 appears to evolve from the canonical γ-aminobutyric acid transaminases and directs the biosynthesis of nitrogen-containing steroidal metabolites in Solanum plants.
Caliendo and Vitu et al. developed a platform for endogenous gene expression monitoring and conditional actuator activation, by integrating noncoding RNAs downstream of the polyadenylation signal without altering endogenous gene coding sequences.
Superoxide oxidizes the iron–sulfur cluster in the DNA demethylase ROS1 and extensively participates in the establishment of active DNA demethylation in plants to maintain stem cell fate.
By enriching productive mutational paths, a Kemp eliminase that speeds up proton abstraction >108-fold was developed in only five evolution rounds. Recombining it with a variant differing by 29 substitutions revealed the underlying fitness landscape.
How a lasso cyclase ties a lasso peptide into its characteristic knot has remained poorly understood. Here the authors identify key molecular interactions that guide lasso peptide folding and cyclase substrate tolerance to inform cyclase engineering for expanded lasso peptide diversity.
Cryo-electron microscopy and biochemical analysis reveal the activation mechanism of protein arginine kinase McsB by its activator McsA for protein quality control under stress in Gram-positive bacteria.
Development of a ligand-based proximity labeling strategy enables interrogation of the native cell membrane interactome for the GLP-1 receptor in two cell types, revealing new regulators of receptor-mediated signaling and β cell responses.
A method to study G-protein-coupled receptor (GPCR) trafficking has been developed using engineered APEX2 and CRISPR interference screening. The innovative approach reveals a network of proteins coordinated by DNAJC13 that control efficient GPCR sorting into degradative or recycling pathways.
Development of a biosensor for GPCR trafficking to the lysosome combined with a genome-wide CRISPR screen identified DNAJC13 as a critical regulator of agonist-induced trafficking of the δ-opioid receptor to the lysosome.
Qiao and Nguyen et al. describe a strategy to block hypoxia-dependent gene expression in cell and mouse models of breast cancer through dual targeting of X-box-binding protein 1 and hypoxia-inducible factor binding to DNA with fully synthetic, stabilized artificial transcription factors.
