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A simple and effective strategy is introduced to increase CRISPR–Cas9-mediated gene knock-in rates by using 5′-modified double-stranded DNA donors with short homology arms.
The authors utilize fluorescence-activated cell sorting coupled with next-generation sequencing, as well as dynamic modeling, to study the molecular mechanism underlying indole signaling and reveal different roles of the two ends of tnaC in coordinating transcription and translation.
UBE2T adopts an allosteric activation mechanism to mediate site-specific ubiquitination of Fanconi anemia complex. Interaction with FANCL induces a cascade of conformational changes of UBE2T and leads to exposure of substrate-binding sites.
An in silico directed evolution approach using first principles of allostery predicts the effects of protein sequence and structure variation on constitutive activity and ligand response in GPCRs.
The ability to engineer synthetic signaling networks has proven challenging for synthetic biology. A breakthrough design strategy shows that bacterial two-component-system-derived parts can be grafted into mammalian cells to create programmable phosphorylation circuitry.
Single-molecule FRET technologies reveal the mechanism of sequence-specific translational inhibition induced by two antibiotics, chloramphenicol and linezolid, where aminoacyl-tRNA was repeatedly rejected from the A-site and failed to form a peptide bond.
Bacterial two-component signaling machinery has been reprogrammed for orthogonal signaling in mammalian cells that is triggered by small-molecule-mediated dimerization or ligand-induced GPCR/β-arrestin signaling.
A combinatorial engineering strategy encompassing pathway regulation, heterologous enzymes and subcellular trafficking enables repurposing of the phospholipid biosynthetic pathway in Saccharomyces cerevisiae for the production of oleoylethanolamide.
The crystal and cryo-electron microscopy structure analysis of the DCAF15–DDB1–DDA1–indisulam–RBM39 complex revealed the detailed mechanism of action of indisulam-induced RBM39 degradation and defined an α-helical degron motif in RBM39.
The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.
Phenotypic screening is an engine of discovery for bioactive small molecules and can unravel novel mechanisms and pathways controlling cellular physiology. A recent study reveals the CPSF complex as a pharmacologically tractable target of JTE-607 and context-specific cancer dependency.
Molecular-glue-mediated proximity-induced degradation now allows unprecedented therapeutic targeting of previously undruggable proteins. Structures showing how aryl-sulfonamides mediate recruitment of the splicing factor RBM39 to the E3 CRL4DCAF15 broaden the mechanistic principles by which molecular glues target ubiquitylation.
An improved workflow combining de novo transcriptome assembly and Ribo-seq validated by cellular antigen display is developed to maximize small peptide discovery, leading to identification of thousands of unannotated protein-coding smORFs.
A photocrosslinking-based nucleosome profiling approach is used to identify a conserved basic motif in the ISWI remodeler SNF2h that anchors it to the acidic patch of nucleosome and enables nucleosome sliding activity.
PUS10 exhibits two different functions: one is to promote miRNA biogenesis in a catalytically independent manner; the other is to install pseudouridine modification in tRNAs in a catalytically dependent manner.
