Mechanism of action articles from across Nature Portfolio

Palmitoylation at C64 in stimulator of interferon genes (STING) is reported and, along with engagement of C91, is involved in dynamic cross talk with C148 to alter STING oligomer states and ultimately control STING activation.

The antibacterial agent colistin displays synergistic activity with azoles and echinocandins against various pathogenic fungi. Here, the authors show that the mechanisms involve disruption of cell membrane permeability and calcium homeostasis.

High-content protein arrays were used to identify cysteine dioxygenase (CDO1) as a small-molecule glue target for the von Hippel–Lindau (VHL) E3 ubiquitin ligase and induces VHL-dependent proteasomal degradation of CDO1 in cells.

Nonselective engagement of GPCR signaling pathways by GPCR-targeting drugs can reduce treatment efficacy and cause side effects. The authors show that signaling selectivity in CB2R can be tuned by reshaping allosteric networks, offering insights for more precise therapies.

Targeting non-apoptotic cell death pathways is an attractive approach for treating apoptosis-resistant cancers. Tegavivint, a drug candidate undergoing clinical trials in different cancers, has been found to trigger a unique cell death pathway that acts via the synthesis of the saturated long-chain fatty acid palmitate.

Essential iron–sulfur cofactors are assembled by multiprotein machineries in most life forms. Now, in vitro reconstitution of the bacterial core machinery has provided snapshots of the early assembly steps and revealed that [2Fe–2S] clusters are formed from two [1Fe–1S] precursors.

We established a mouse model of progressive aortic aneurysm induced by conditional Notch1 deficiency in vascular smooth muscle cells. Notch1 deficiency impairs the transcription of genes involved in mitochondrial fusion and biogenesis, thereby triggering aortic pathology. Early intervention to enhance these mitochondrial processes could potentially slow disease progression.

Enabling protein degradation with small-molecule drugs has emerged as an innovative approach to the development of therapeutics against otherwise intractable targets. Two landmark studies that established the therapeutic potential of heterobifunctional degrader molecules are celebrating their 10-year anniversary.

Prokaryotic CRISPR–Cas systems are counteracted by phage-encoded anti-CRISPR elements, and how they protect themselves remains enigmatic. A study shows that CRISPR-repressed toxins defend CRISPR–Cas against anti-CRISPR proteins or RNAs by inducing abortive infection.

Two recent studies identify derivatives of (+)-JQ1, a non-degrading inhibitor of BET bromodomains, as molecular glues that recruit DCAF16 and DCAF11 via mechanisms involving stabilization of transient target–ligase interactions.