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Reliably identifying ubiquitin ligase interactors and substrates has been a persistent challenge in cellular biology. A breakthrough comes in the form of a potent, selective and cell-active chemical probe, shedding light on the intricate functions of a key regulatory enzyme.

Owens et al. reported PFI-7, a selective and potent antagonist of GID4 of the CTLH E3 ligase complex, which enables identification of human GID4 targets. This study provides valuable insights into GID4 functions and a powerful tool for advancing new targeted protein degradation strategies.

Yin et al. discover that the phosphatase PTENα acts as an RNA-binding protein, mitigating viral-induced inflammation in the brain by constraining RIG-I activation, suggesting PTENα as a potential therapeutic target for viral infection.

A newly developed maternally selective nanobody antagonist against the angiotensin II type I receptor stabilizes the receptor in a hybrid conformation and simultaneously binds with specific small-molecule antagonists.

Biochemical pathways for aromatic amino acid synthesis are ancient and highly conserved. Directed evolution of the β-subunit of tryptophan synthase (TrpB)—a proficient biocatalyst that converts indole to l-tryptophan—enabled this enzyme to make l-tyrosines from phenols, a pathway not (yet) known in nature.

Natural ribozymes can cleave RNA and single-stranded DNA (ssDNA) by transesterification or a blend of hydrolytic and transesterification reactions. Now, ribozymes have been discovered that catalyze the hydrolytic cleavage of ssDNA. Similar ribozymes could potentially replace large, immunogenic, protein-based nucleases in gene therapies.

Ferroptosis, a cell death mechanism induced by lipid peroxidation, is pivotal in tumor suppression. A recent study shows that tumor repopulating cells evade ferroptosis and develop resistance to therapy via subverting a lipid metabolism enzyme.

Phosphorylation of ACSL4 by mitochondria-located metabolic kinase PCK2 is critical to regulating ferroptosis-associated phospholipid remodeling in tumor-repopulating cells that are resistant to chemotherapy and radiotherapy.

We present a discovery pipeline integrating chemical fragment screening and time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS). This approach identifies allosteric chemical leads targeting distinct allosteric states of the mitochondrial oxidoreductase apoptosis-inducing factor (AIF). By monitoring kinetic rates of allosteric transition with TR-HT-SAXS, we link fragment structure–activity relationships (SARs) to biomolecular conformation.

CRISPR–Cas13 systems use single-subunit RNA-guided Cas13 effectors for targeted RNA recognition and cleavage. This Review summarizes the recent advances in understanding the structural and mechanistic aspects of Cas13 systems and the diverse applications of these systems in biotechnology and therapeutics.

A discovery pipeline integrating time-resolved HT-SAXS and fragment screening identifies chemical leads targeting exemplary allosteric states of mitochondrial oxidoreductase apoptosis-inducing factor (AIF).

Understanding the role of pyrophosphorylation requires specific analytical strategies to discriminate it from protein phosphorylation. A custom workflow reveals that nucleolar protein pyrophosphorylation in human cells regulates the transcription of ribosomal DNA.

A small-molecule iron mobilizer, FeM-1269, minimally higher-order aggregates in aqueous media and effectively mobilizes iron across a range of concentrations. FeM-1269-promoted iron mobilization restores physiology in animals at well-tolerated doses.

A tailored proteomics workflow to identify endogenous protein pyrophosphorylation in human cells was developed, revealing the dependence of the modification on inositol pyrophosphates and a putative function in rDNA transcription.