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Two programs, GRAPE and GARLIC, work together to first predict biosynthetic gene clusters responsible for the production of polyketides and nonribosomal peptides, then link sequenced gene clusters to known and unknown natural products.
A high-throughput screen identifies NGI-1 as an inhibitor of oligosaccharyltransferase, preventing transfer of N-linked glycans to proteins. NGI-1 blocked EGFR signaling in non-small-cell lung cancer cell lines and promoted cell-cycle arrest and senescence.
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.
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.
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.
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).
High-throughput screening identified a small-molecule compound that targets the active conformation of HER2 and is effective against growth-factor-mediated drug resistance.
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.
A small molecule inhibits CDK12 and CDK13 activity through covalent modification of Cys residues and reveals a role of the two kinases in regulating Pol II processivity and super-enhancer-driven transcription factor and DNA damage response gene expression.
Biochemical and genetic strategies demonstrate that the antifungal natural product beauvericin targets both multidrug efflux and TOR signaling to limit drug resistance and to sensitize resistant pathogens to drug treatment during infection.
Probes based on the photoactive yellow protein tag for monitoring the consequences of glycosylation on GLUT4 traffic reveal that glycosylation is important for plasma membrane retention of the glucose transporter.
A high-throughput screen using a mass-spectrometry-based assay results in the identification of LRE1 as an inhibitor of HCO3−/Ca2+-regulated soluble adenylyl cyclase activity. LRE1 interacts with the HCO3− binding site (BBS) to block cAMP formation.
Detailed biophysical, microscopy, and statistical analyses of hydrocarbon-stapled peptide variants revealed how a combination of critical parameters such as hydrophobicity, α-helicity and isoelectric point influence cellular permeability.
A combination of statistical analysis, quantum mechanics calculations and biophysical analytical approaches shows that methionine oxidation increases its interactions with aromatic side chains, interactions that are important for intraprotein and interprotein interactions.
The LARGE glycosyltransferase generates a repeating disaccharide on α-dystroglycan, an extracellular matrix receptor essential for muscle function. A structural study defines a unique binding mode between the LARGE-generated oligosaccharide and the matrix protein laminin.