Reviews & Analysis

A new small molecule that targets the vacuolar H⁺-ATPase activates autophagy, inhibits mTORC1 signaling, and displays potential for clearing toxic protein aggregates involved in neurodegenerative diseases.

Autophagy is a ‘self-eating’ recycling process that maintains cellular homeostasis. Autogramins were identified as small-molecule autophagy inhibitors that target the cholesterol transport protein GRAMD1A, revealing a role for cholesterol in autophagosome biogenesis.

The limited availability of small-molecule ligands for E3 ubiquitin ligases stymies the development of next-generation degraders. Two recent papers report the identification of novel, covalent and PROTAC-compatible ligands that hijack the previously untargeted ligases RNF114 and DCAF16.

This Review highlights recent structure–function insights that inform diverse pharmacologic strategies for direct targeting of BAX to alternatively reactivate or inhibit apoptosis in diseases of pathologic cell survival or premature cellular demise.

The advent of PROTACs that degrade the entire protein target rather than simply inhibiting it bring druggable yet apparently non-functional binding sites into play for medicinal chemists to do their work.

The NLRP3 inflammasome contributes to pathogenic inflammation in a broad range of diseases, making it a highly relevant drug target. Two studies published in this issue found an inhibitor of NLRP3 inflammasome activation to directly bind NLRP3 within its central NACHT domain, interfering with ATP hydrolysis and structural changes critical for NLRP3 oligomerization and subsequent inflammasome formation.

Endocytosis mediates the internalization of proteins and lipids at the plasma membrane and plays essential roles in plant growth and development. A new small molecule enables manipulation of plant endocytosis in an acute and transient manner.

Chemical probes that irreversibly inhibit protein function may be used across species to discover proteins. Combining phenotypic screening and activity-based protein profiling, a new study uncovers a discrete lipid signaling pathway regulating lifespan in the worm Caenorhabditis elegans.

Arginine protein kinases regulate bacterial signaling cascades through phosphorylation of key arginine residues. Crystal structures of the kinase McsB provide the first glimpse of how these unusual enzymes recognize their protein substrates and are allosterically regulated.

The molybdenum cofactor (Moco) is a fragile prosthetic group essential for most organisms. Nematodes are now capable of extracting Moco from their bacterial diet to mediate detoxification of sulfite.

Powerful combinatorial peptide library methods allow the discovery of peptide leads from diverse libraries. A new platform based on tandem mass spectrometry peptide sequencing coupled with high-performance size-exclusion chromatography enables identification of high-affinity peptidic ligands from focused libraries.

The N⁶-methyladenosine modification next to the 5′ RNA cap has dynamic regulatory functions. Recent findings show that this modification regulates the splicing and translational activity of different classes of RNAs.

Potassium channels allow the passage of potassium ions across membranes at rates approaching the diffusion limit while maintaining exquisite selectivity between ion species. Single-molecule studies now reveal that the selectivity filter of these proteins transitions between different conformations.

A small molecule was identified that binds to a unique site on the pro-apoptotic protein BAX, stabilizing the protein structure allosterically and preventing the conformational activation to a pore former by BH3 proteins.

A new method introduces ubiquitin or ubiquitin-like proteins at specific sites in any protein without the requirement of the cellular ubiquitylation machinery. This will help decipher the code by which these modifications control cellular processes.

Cell envelope assembly during V snapping, an unusual method of cell division in Actinobacteria, is mechanistically different than that seen during cell division of many other bacteria.

Holliday junction resolvases lock dynamic DNA four-way junctions into specific structural conformations for symmetric DNA cleavage. Single-molecule studies now reveal that resolvases can relax their grip, enabling Holliday junction conformer transitions and branch migration in the enzyme-bound form.

A collection of genetically encoded tools, each with their own capabilities, limitations and performance characteristics, are available for monitoring and manipulating neuronal activity that could allow visualizing the brain at single-cell resolution.

Faster-than-transcription control of cellular activities is an important but challenging engineering target. Using split ferredoxins and induced dimerization or conformational changes, newly developed metalloprotein switches provide a fast method to control electron flux.

Two protein circuit systems, split-protease-cleavable orthogonal coiled-coil logic (SPOC logic) and circuits of hacked orthogonal modular proteases (CHOMP), have been developed to permit rapid and logic function-based control of mammalian cellular signaling.