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A new study reports THZ531 as a covalent CDK12/CDK13 inhibitor affecting transcription. Application of the compound in cells decreases transcription elongation of DNA damage response genes and key super-enhancer-associated transcription factor genes, with important implications for targeted cancer therapy.
Scientists find that oxidation of methionine induces favorable interactions with aromatic groups in proteins, contrary to conventional wisdom, providing new molecular insight into the structural and biological impact of methionine oxidation.
Stapled helices are promising compounds for inhibiting intracellular protein–protein interactions, but the discovery of peptides with the key property of cellular uptake has taken place largely through trial and error. A new study defines physicochemical parameters for designing hydrocarbon-stapled helices with a greater likelihood of cellular uptake.
Nikkomycins and polyoxins are peptidylnucleosides with antifungal activity. The biosynthetic routes to these natural products share a bicyclic intermediate formed by a carbon radical–centered ring closure catalyzed by the radical SAM enzymes NikJ or PolH.
A high-throughput screen against the E. coli tetracycline-resistance efflux pump TetA identifies two ‘selection-inverting’ compounds that swap tetracycline resistance for resistance to another antibiotic, paving the way for two-phase antibiotic treatment protocols.
A SH2-domain-derived superbinder that exhibits strong affinity for phosphotyrosine (pTyr) was used in conjugation with mass spectroscopy approaches to enrich and enable identification of pTyr sites in different cancer cell lines.
Transplantation of the prokaryotic LysR-type transcriptional regulator into yeast combined with in vivo screening identifies yeast mutants that produce metabolic products with bacterial small molecule inducers.
The application of high-resolution metabolomics integrated with isotope labeling revealed that lactate is imported into the mitochondria and is metabolized by mitochondrial LDH into pyruvate.
The glycosyltransferase OGT cleaves a substrate, HCF-1, via a glutamyl-sugar intermediate, defining a reaction mechanism that requires UDP-GlcNAc and involves the formation of an internal pyroglutamate that undergoes spontaneous backbone hydrolysis.
Analysis of the structures and dynamics of intermediates and engineered mutants from directed protein evolution experiments reveals how dynamic conformational changes are harnessed across evolutionary trajectories to generate new catalytic functions.
A modified version of Cas9 with a fusion of the hormone-binding domain of the estrogen receptor allows reversible control of Cas9 activity with high efficiency at multiple loci with 4-hydroxytamoxifen treatment.
Combining the kinetic separation capability of capillary electrophoresis with the structural elucidation capacity of ion-mobility mass spectrometry, a coupled CE–UV–IM–MS system demonstrates utility in examining transglutaminase conformers and their enzymatic activity.
The use of an aryl boronic acid carbonyl warhead to target a noncatalytic lysine side chain enables the development of covalent inhibitors against the anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1).
