Aromatic side-chain crosslinking is emerging as a widespread and biosynthetically diverse feature in the RiPP natural products. This Review summarizes and unifies recent advancements, focusing on key enzymes that catalyze these modifications.

This Perspective highlights how metabolic states regulate diverse protein modifications that affect physiology. In addition, the roles of subcellular localization of metabolic enzymes and the importance of untargeted omics approaches are discussed.

Cellular recording in DNA memory is an emerging and promising strategy to document the biological activity of individual cells over time. A prime editing-based recording system using prime-editing guide RNAs (pegRNAs) has been developed to track cellular histories by making sequential insertions in the genome of mammalian cells.

Targeting of protein aggregates is technologically challenging. We developed a phage-assisted continuous evolution platform for rapid selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli. This strategy enabled discovery of cyclic peptides that suppress the aggregation of two clinically relevant proteins, amyloid-β42 (Aβ42) and human islet amyloid polypeptide (hIAPP).

A small-molecule agonist of transient receptor potential cation channel subfamily M member 4 persistently activates the ion channel and induces necrosis characterized by sodium overload.

A biosynthetic binary population of membraneless compartments is engineered to mimic membraneless organelles and is capable of delivering molecular messages with controllable feedback under cellular environmental conditions.

Protein kinase R-like endoplasmic reticulum kinase-phosphorylated adenylosuccinate lyase (ADSL) binds to Beclin1 upon lipid deprivation. ADSL-produced fumarate increases Beclin1 K117 dimethylation by inhibiting lysine demethylase 8 activity, resulting in disrupted binding of BCL-2 to Beclin1, enhanced autophagy and liver tumor growth.

Here, Kropp et al. use cryo-electron microscopy and structural modeling to show that the enzyme [MoCu]-CO dehydrogenase interacts with its partner, the membrane-bound quinone-binding protein CoxG, to facilitate electron transfer from atmospheric CO oxidation to the respiratory chain. This interaction is conserved across diverse bacteria and archaea.

Iron–sulfur clusters are essential protein cofactors synthesized through a complex sequential process. Here the authors show that the assembly of [2Fe–2S] clusters by the iron–sulfur cluster assembly machinery proceeds by the formation and fusion of [1Fe–1S] intermediates in the IscU scaffold protein.

ARAF uniquely enhances RAS activity via N-terminal disordered sequence, forming membrane ARAF–RAS condensates that shield RAS from negative regulation and drive cancer drug resistance.

To celebrate the start of our 21st volume, we are featuring a collection of pieces that discuss the progress in chemical biology over the past 20 years. These pieces highlight some of the landmark findings that have shaped the field and outline future directions.

The field of chemical biology has changed dramatically over the past 20 years. Here, we speak to Sarah E. O’Connor, Benjamin F. Cravatt and Chengqi Yi about the major changes that have affected the field, the advances that have affected them and their research, and their thoughts about the most important questions currently facing chemical biologists.

As Nature Chemical Biology approaches its third decade we asked a collection of chemical biologists, “What do you think are the most exciting frontiers or the most needed developments in your main field of research?” — here is what they said.