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Hydrogen exchange–mass spectrometry (HX–MS) is used to qualitatively assess how perturbations such as mutations and ligand binding impact protein ensembles. However, in theory, HX–MS data contain the information necessary to derive residue-level energies of local unfolding (ΔGop). Now, a method called PIGEON-FEATHER has been developed, which can unambiguously determine residue-level ΔGop from conventional HX–MS datasets.
Phenotypic screening of an endophyte-derived compound library led to identification of a potent anti-non-small cell lung cancer (NSCLC) lead compound, the 3,4-diisobutyryl derivative of auxarthrol A, uncovering dynein light intermediate chain 1 as a druggable vulnerability and a key regulator of autophagy in NSCLC.
Hydrogen peroxide is a signaling molecule that can also cause damage if its levels are too high. Here, the authors report HyPerFLEX, a fluorescent sensor with tenable colors, to track very low peroxide levels in cellular organelles, even in low-oxygen or highly oxidizing environments.
Duan and Kaushik et al. reveal the structural basis of how Escherichiacoli and Thermusthermophilus RNA polymerases initiate transcription from Np4A alarmones producing Np4-capped transcripts. The caps form various interactions with a polymerase during initial steps, influencing capping efficiency.
Programming stimulus responsiveness into living systems enables advanced biocomputation. Here, the authors autonomously compile proteins with defined topology that can be site-specifically tethered to and conditionally released from biomaterials and cells following user-specified Boolean logic.
Zhu, Fu, Zhu, Li and colleagues found that the key DNA repair enzyme poly(ADP-ribose) polymerase 1 promotes transcriptional restart after DNA damage through PARylating and stabilizing AFF1 by preventing its ubiquitylation by the E3 ligase Siah1.
This study presents prime-editing-based inversion with enhanced performance, a prime editing-based system that enables efficient and precise genomic inversions from kilobase to chromosome scale, offering a powerful tool for chromosomal engineering, disease modeling and studying three-dimensional genome architecture.
In plants, oxidosqualene cyclases (OSCs) perform a highly complex single reaction to generate the basis of all triterpenoid diversity. Here the authors leverage genome mining and transient expression to uncover multiple evolutionary and mechanistic insights for OSCs across the plant kingdom.
Engineered aminoacyl-tRNA synthetase (aaRS) mutants have been developed that facilitate ultrafast bioorthogonal noncanonical amino acid tagging (BONCAT) of newly synthesized proteins in diverse bacteria, including ESKAPE pathogens. The substrate polyspecificity of the aaRS mutants enables pulse-chase BONCAT and differential tagging of temporally distinct nascent proteomes in cells.
Low-antigen-expressing cancers are a challenge to existing chimeric antigen receptor (CAR)-T cell-based therapies. Now, it has been shown that fusion of intrinsically disordered regions to CARs induces CAR condensation and enhances antigen sensitivity and killing activity of CAR-T cells.
Static protein structures can capture the association of lipids, but it is unclear whether the association is due to lipids acting as long-lived ligands or the solvation of preferred lipids around the protein. A computational-experimental framework has now shown that for the protein CLC-ec1, it is the change in lipid solvation energies that drives dimerization, with preferred lipids around the protein modulating this driving force.
The development of soluble Notch agonists is a challenge because of the mechanical forces needed to activate Notch receptors. Here, bispecific Notch agonist proteins were designed that ‘pull’ on and activate Notch receptors in the presence of desired biomarkers.
Smargon et al. show that small nuclear RNAs can improve the cellular safety and efficacy of endogenous protein-mediated RNA base editing, enhancing nuclear RNA editing and the rescue of premature termination codon disease.
An approach combining bioorthogonal chemistry with genetically encoded fluorogen-activating proteins enables subcellular imaging of phospholipids and glycans, as well as the visualization of lipid transport between organelles and lipid asymmetry across membrane leaflets.
Inhibition of ELOVL6, a fatty acid elongation enzyme, selectively degrades mutant KRAS, disrupts its membrane localization and suppresses tumor growth, revealing a novel vulnerability in KRAS-driven cancers.
Designer box H/ACA RNA-guided pseudouridylation can target both mRNA and tRNA. Modifying the first U of a stop codon and U36 of the matching anticodon forms one Ψ–Ψ and two Watson–Crick pairs, enabling efficient and specific stop codon readthrough.
The use of bulky protein tags and the limited positions available for probe introduction restrict current methods for studying protein microenvironments at high spatial resolution. Here the authors genetically incorporate small environment-sensitive fluorescent amino acids to visualize real-time microenvironmental changes at specific protein substructures.
Using computational and experimental methods, Ouyang and Chen et al. reveal a drug design principle that the hydrophobic properties of small-molecule drugs significantly influence their ability to engage with and effectively target phase-separated proteins.
Many animals display brilliant colors thanks to the precise formation of guanine crystals within specialized organelles. Here, the authors demonstrate that dynamic pH shifts orchestrate this process: an initially acidic lumen stabilizes amorphous, protonated guanine and subsequent alkalinization triggers its crystallization.
