Reviews & Analysis

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.