This Perspective discusses click biology as an analogy to click chemistry and examines reactions carried out using building blocks present in every living cell, enabling rapid selective covalent bond formation under biologically friendly conditions. Desirable criteria for robust cellular performance are defined, along with new opportunities arising from click biology for fundamental research and synthetic biology.

This Review highlights recent advances in understanding compartmentalized GPCR signaling using chemical biology approaches with a focus on tools for real-time monitoring, site-selective tuning of signaling protein networks and mechanistic screening.

This Review discusses the existing approaches for chemical reprogramming to induce pluripotency and totipotency through alterations in epigenetic regulation and the key challenges and future application prospects.

Molecular glue degraders are small molecules that have major therapeutic potential. Here, protein microarrays enabled the identification of proteins that can be glued to the VHL E3 ligase and degraded with VHL targeting ligands.

The primary entry route of vanilloid ligands to the vanilloid-binding site in transient receptor potential vanilloid 1 (TRPV1) is found to be a distinct and targetable hydrophobic pathway at the TRPV1–cell membrane interface rather than through direct membrane penetration.

Monoterpene indole alkaloids are formed via a 3S stereoselective condensation between secologanin and tryptamine. Here the authors uncover the mechanism of epimerization behind uncommon 3R-containing alkaloids in Mitragyna speciosa (kratom) and study their inclusion in downstream biosynthesis.

Glutarate rewires cell metabolism through conjugation to proteins or fatty acids, but how glutarylation is regulated is unclear. ABHD11 was identified as a lipoyl-deglutarylase to maintain the TCA cycle and mitochondrial metabolism.

Ligands that recognize the amyloid-β (Aβ) oligomers implicated in Alzheimer disease could be useful for diagnostic and therapeutic applications. However, discovering such binders is challenging because of the difficulty of measuring oligomer-binding activity. A strategy has now been reported to detect binding to Aβ42 oligomers, which is used to select new binders with improved potency.

Legionella effector LtpM is found to recognize short two-residue sequons, enabling site-specific O-glucosylation with minimal perturbations to a target protein, and is used to show that O-glucose can act as a constitutively active O-linked N-acetylglucosamine mimic.

Molecular recorders based on kinase activity-dependent protein labeling track specific kinase activities to understand their link to cellular phenotypes in heterogeneous cell populations and in vivo.