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A biosensor based on the GABAA receptor with a readout consisting of quenching and recovery of biomolecular fluorescence in live cells is used in a screen to identify new interacting ligands for the receptor benzodiazepine site.
Structural, enzymatic and cellular target engagement studies reveal the mechanism of action by N-hydroxyurea small molecule inhibitors of the DNA repair enzyme, human flap endonuclease-1 (FEN1) that prevent cleavage of DNA flaps in cancer cells.
A single-molecule approach demonstrates that TALEs scan DNA using a unique ‘zip-line’ mechanism wherein the TALEs move without rotating along the DNA helix, yet the DNA remains threaded through the loosely wrapped TALE.
A cyclobutane compound competitively inhibits the activity of androgen receptors (AR) containing antiandrogen-resistant mutations through stabilization of the receptor in an apo-like conformation and preventing AR nuclear entry.
The modification of Cdc42 with a FRET binding antenna (GDI.Cdc42 FLARE) enables detection of Cdc42 binding to guanine-nucleotide dissociation inhibitor (GDI) and Cdc42 activation with improved spatial-temporal resolution during cellular protrusion and retraction.
The application of a potent lactate dehydrogenase (LDHA) inhibitor GNE-140 on pancreatic cancer cells revealed that resistance to GNE-140 is attributable to an AMPK–mTOR–S6K-mediated switch in utilization from glycolysis to oxidative phosphorylation.
Analysis of the hydrolysis kinetics of strigolactone receptors using enzyme-activated fluorescent probes revealed that the catalytic triad histidine of the receptor forms a covalent interaction with the strigolactone hydrolysis product, the D ring.
A photoswitchable diacylglycerol enables spatiotemporal control of membrane translocation of C1-domain-containing proteins and protein kinase C activation to modulate calcium oscillations and vesicle release for synaptic transmission.
Histone deacetylase 6 (HDAC6) is a cytoplasmic HDAC that is unusual in having two adjacent catalytic domains. Kinetic data and X-ray crystallographic analyses of human and zebrafish HDAC6 enzymes provide insight into HDAC6 catalysis and its inhibition by small molecules.
X-ray crystallographic analysis reveals features of the tandem catalytic domains of histone deacetylase 6 (HDAC6), their inhibition by small molecules and functional insights into the enzyme's role in tubulin deacetylation.
A small-molecule screen examining the inhibition of Arabidopsis hypocotyl growth and seed germination identified an antagonist of strigolactone signaling, soporidine, that interacted with the strigolactone receptor AtHTL and blocked Striga germination.
Structural and biochemical studies of the Notch O-glucosyltransferase Rumi in complex with its substrates inform on the catalytic mechanism for Rumi substrate recognition, and characterization of cancer mutations in Rumi reveals loss of enzyme activity.
Rational design of the RNA recognition motif (RRM) of Rbfox promotes sequence-specific interaction with the terminal loop of miR-21 precursor. Replacement of the Dicer PAZ domain with this engineered Rbfox RRM enables specific degradation of pre-miR-21.
Structural and biochemical studies of the bacterial NAD-decapping enzyme, NudC, in complex with NAD or its cleavage product NMN reveal the critical residues for substrate recognition and the preference of NudC for NAD-capped RNA.
Structural and biochemical analysis of the recently discovered env25 pistol ribozyme reveal an active site containing a pseudoknot that enforces in-line nucleophilic attack at the scissile phosphate and positions nucleotides for general acid and general base catalysis.
Evolution of RNA aptamers that act allosterically by recognizing and stabilizing specific conformations, including active, inactive, and ligand-specific conformations of the GPCR β2-adrenergic receptor, bound to pharmacologically distinct ligands.
Acute myeloid leukemia (AML) cells require BRD9 to regulate MYC gene expression and prevent myeloid differentiation. Selective inhibition of BRD9 using a chemical probe that was validated using a resistant bromodomain-swap allele of BRD9 limits AML cell growth.
The use of activity-based chemical probes revealed that Scribble is palmitoylated at cysteine residues by the palmitoyl acyltransferase ZDHHC7. Loss of Scribble palmitoylation results in loss of cell polarity and its tumor suppressor activity.
A reactivity-based probe containing an iron-sensitive 1,2,4-trixolane ring conjugated to a small molecule payload combined with a high-throughput immunofluorescence assay enables the selective detection of labile intracellular ferrous iron.