Browse Articles

A new study combines massively parallel assays, transcriptomics and biophysical modeling to provide a framework for analyzing the effects of compounds that modulate pre-mRNA splicing. The results lend important insights into the mechanisms of drug action and facilitate the design of splicing therapies.

RAS proteins, central drivers of cancer, appeared ‘undruggable’ for almost 30 years. Here we provide a personal perspective on the effort leading to our initial report of KRAS^G12C inhibitors in 2013, and the decade of discoveries that followed.

An examination of metabolic changes during B cell differentiation reveals that germinal center B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2-mediated one-carbon metabolism, resulting in increased availability of nucleotide precursors and antioxidants.

Zhu et al. found that cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. Phospholipid synthesis acts as an integrative defense mechanism to sense and combat oxidative stress.

β-Lactam antibiotics are detected by the sensor domain of BlaR in methicillin-resistant Staphylococcus aureus. A class of inhibitors has been developed that targets this sensor domain and prevents downstream activation of the antibiotic response pathway.

We combine RNA thermometer genetic switches, cell-free protein expression and synthetic cell design to create cell-sized systems that can initiate the synthesis of soluble proteins at defined temperatures. We show that when these switches are used to control the expression of a pore-forming membrane protein, temperature-controlled cargo release is achieved, with potential future applications in biomedicine.

Soapwort (Saponaria officinalis) is a rich reservoir of triterpenoid glycosides that often have important pharmaceutical, nutraceutical and agronomical potential. Here, the authors elucidate the complete biosynthetic pathway of saponarioside B, a major saponin constituent in soapwort.

SMAD ubiquitylation regulatory factor 1 (Smurf1) was identified as a critical activator of the phosphoinositide 3-kinase (PI3K)–Akt pathway by promoting phosphoinositide-dependent protein kinase 1 (PDK1) neddylation and cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) assembly. Smurf1-antagonizing repressor of tumor 1 (SMART1), a highly selective degrader for Smurf1, was developed and suppressed the tumor growth of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant colorectal cancer.

Hybrids of macrolides and quinolones, called macrolones, can overcome macrolide-induced resistance through new interactions between the quinolone moiety and the ribosome and can concurrently inhibit both ribosome and DNA gyrase targets.

The field of engineered living materials (ELMs) involves incorporating cells into materials to enable new functionalities. Now, ELMs have been developed that facilitate inter-kingdom communication between bacteria and eukaryotic cells using transcriptional regulation and extracellular electron transfer.

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.

Using a combination of antibody- and LC–MS/MS-based methods, Zhang et al. reveal lysine l-lactylation as the key lactylation isomer in cellular histones, responding dynamically to glycolysis and positively correlating with lactyl-CoA levels, providing insights into the Warburg effect.

Protein misfolding can spread from one molecule to another in infectious prion diseases. The propagation of protein misfolding has been directly observed in single protein molecules. These results showed that pathogenic mutants of the protein superoxide dismutase-1 (SOD1), which causes familial amyotrophic lateral sclerosis, imprint their misfolding onto native wild-type molecules.

Biological reduction of dinitrogen by nitrogenase requires high-energy electrons to form ammonium ion. A new study reveals the structure and function of a molecular machine that exploits the proton-motive force to provide a powerful reductant used by the nitrogen-reducing system of the soil bacterium Azotobacter vinelandii.

González-Delgado et al. developed retron-based editors termed multitrons, which can modify multiple sites on a single genome simultaneously. This technology is compatible with recombineering in prokaryotes and CRISPR editing in eukaryotes with applications in molecular recording, genome minimization and metabolic engineering.

In type I-F CRISPR–Cas systems, Cas2/3 is typically recruited to the interference complex Cascade by Cas8f. We resolved the structures of the phage ICP1 CRISPR–Cas complexes and discovered a Cas2/3 recruitment mechanism distinct from that in other type I-F systems — recruitment by Cas1.

Time-resolved synthesis of target proteins via proximity-triggered protein trans-splicing has now been shown to enable the activation of a diverse set of proteins upon the addition or removal of control elements. This temporal precision allows for monitoring distinct phases in cellular signaling and unveiling the molecular connections of oncofusion kinases, including DNAJ–PKAc.

By engineering a tiny OgeuIscB–ωRNA system and tethering DNA-binding protein Sso7d, the authors developed robust miniature base editors SIminiBEs, which achieved robust C-to-T and A-to-G base transitions with a broad targeting range.

The ICP1 (International Center for Diarrheal Disease Research, Bangladesh cholera phage 1) clustered regularly interspaced short palindromic repeats (CRISPR)–Cas system, which lacks the helical bundle domain in Cas8f, uses Cas1 to mediate the interference stage by connecting Cas2/3 to the DNA-bound CRISPR-associated complex for antiviral defense (Cascade).

Through rational protein engineering and structure-guided ωRNA engineering, the ωRNA-guided endonuclease IscB system was developed into a highly efficient and compact genome-editing tool.