Reviews & Analysis

This study provides a chemical framework of sulfur, defining the cysteine redoxome, linking thiol reactivity with oxoform kinetics/dynamics to proteome-wide mapping, occupancy and flux, and revealing cysteine oxidation as a programmable regulatory code.

This Perspective highlights advances in bioluminescence resonance energy transfer technologies for measuring intracellular drug–target engagement, expanding their use to analyze kinetics, permeability and complex mechanisms in chemical biology.

This Perspective discusses how elevated-temperature crystallography uncovers hidden dynamic states of protein, ligand and water molecules, expanding insights into the protein conformational landscape for drug discovery and design.

The development of antibody–drug conjugates remains a challenge in part due to the lack of three-dimensional structural information that must account for the inherent flexibility of antibodies and drug payloads. This Perspective discusses computational methods to guide the design of antibody–drug conjugates.

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.

Protein conformational entropy plays a vital role in functions like binding and catalysis. This Perspective discusses three ways macromolecules use conformational entropy: prepaying entropic costs, redistributing entropy and populating catalytically competent ensembles. Future directions for harnessing conformational entropy to control binding, catalysis and allostery are also outlined.

This Perspective discusses recent strategies to expand the scope of targeted protein degradation (TPD) and the implications of unexpected convergence of diverse screening efforts on a small subset of TPD-competent E3 ligases in the human proteome.

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.

Biofouling causes a huge economic loss to our society. This Perspective examines the biofouling process from microfouling to macrofouling, discusses a spectrum of chemical signals that induce and inhibit biofouling and argues for potential management by targeting the signaling responsible for biofilm dispersion or biofouling inhibition.

This Perspective discusses how macromolecular condensation can regulate the electrochemistry to affect biological function in living cells and provides a framework to study the electrochemical functions of biomolecular condensates.

This Perspective discusses the application of algorithmic methods throughout the preclinical phases of drug discovery to accelerate initial hit discovery, mechanism-of-action elucidation and chemical property optimization.

This Perspective proposes practical guidance to the application of AlphaFold2 for structure prediction of different classes of proteins including rigid globular proteins, intrinsically disordered proteins and alternative conformational states. The use of evaluation metrics to predict reliability of the resulting models and their integration with experimental data are also discussed.

This Perspective details how genome-wide association studies and metabolomics enabled the discovery of structures, bioactivities and pathways of modular metabolite biosynthesis originates from the ‘hijacking’ of conserved detoxification mechanisms by nematodes.

This perspective proposes general strategies for phase-separation-related biological studies, including proper experimental designs to validate and characterize phase-separation phenomena, connections to biological functions and some caveats to avoid common misunderstandings.

Loss of myelin causes neurological symptoms for patients with multiple sclerosis. This Perspective details how phenotypic screening has accelerated discovery efforts toward potential ‘remyelinating therapeutics’.

Emerging evidence shows that ubiquitination can occur on nonlysine residues and nonproteinaceous substrates. This perspective summarizes the recent discoveries in noncanonical ubiquitination and advocates the development of chemical biology tools for new substrate identification and mechanistic dissection.

This Perspective discussed selective partitioning behaviors of biomolecules and small molecules and proposed that understanding the chemical properties that control their interactions within the condensates would promote drug development.

New research has revealed a wealth of small molecules that target cancer-specific metabolic vulnerabilities by targeting allosteric sites. Here, a Perspective discusses how their application has provided insights into cancer metabolism and therapy.

This Perspective discusses the genetically encoded tools for measuring and manipulating metabolism, highlighting the tools that are available, guidelines for their use and key areas for future development.

Synthetic receptor signaling systems have evolved as platforms for user-controlled programming of cellular functions. This Perspective reviews these advances and defines a metrics-based engineering workflow to support future engineering efforts.