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A new study enables CRISPR–Cas9-mediated genome modification in a temporally regulated manner. The cover features a modified Cas9 enzyme containing four copies of the hormone-binding domain of the estrogen receptor (lower panel with red and brown squares) that is inactive (faded outline) in the absence of the estrogen-receptor ligand 4-hydroxytamoxifen (4-HT). The addition of 4-HT stimulates Cas9 activity (upper panel with green squares), enabling genome editing to occur. Cover design by Erin Dewalt, based on an image created by Muhammad Nadzim Bin Ramli. Article, p980
Roger Tsien left us on August 24. His untimely passing has saddened and shocked the scientific community. Roger literally and figuratively brightened our world, illuminated the dark matter of biology, and forever changed our view of the interface of chemistry and biology.
The mechanisms by which proteins evolve new functions can be slow and mysterious. Comprehensive structural analysis of enzyme variants reveal how gradual enrichments of pre-existing populations with the right productive dynamics for new functions can accomplish this aim.
The rapid spread of antibiotic-resistant bacteria demands novel treatment approaches that delay or even reverse the evolution of resistance. A new screening strategy identifies two compounds that select against a common tetracycline-resistance gene in Escherichia coli.
Proteolytic maturation of an important transcriptional regulator is performed by a glycosyltransferase. The reaction involves glycosylation of a glutamate residue and conversion of the γ-glycosyl ester product into an N-acyl pyroglutamate, which undergoes spontaneous hydrolysis to effect peptide backbone fission.
A novel approach recruits the largest prokaryotic family of ligand-induced transcriptional regulators to develop a new class of biosensors in yeast based on transcriptional activation, vastly expanding the repertoire of biosensors that could function in eukaryotic hosts.
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.
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.
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 chemoproteomics approach utilizing the thermal shift assay and quantitative MS resulted in the identification of phenylalanine hydroxylase as an off-target of the histone deacetylase inhibitor panobinostat.
An AFM-based single-molecule approach shows how the chaperone and insertase YidC stabilizes E. coli LacY in the unfolded state and assists LacY to insert and fold transmembrane structural segments in random order until folding of the native state is complete.
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.
High-throughput screening identified a small-molecule compound that targets the active conformation of HER2 and is effective against growth-factor-mediated drug resistance.
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).
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.
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.
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.
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.
Vzb22, an amino-group carrier protein from Streptomyces, is required for biosynthesis of the noncanonical amino acid DADH, a biosynthetic precursor of vazabitide A and related azabicyclohexane natural products.
Biosynthesis of the protease inhibitor microviridin J includes peptide macrocyclization catalyzed by two enzymes of the ATP-grasp family. Structures of these macrocyclases, MdnB and MdnC, reveal how they recognize their precursor-peptide substrates.
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.