Glucocorticoid compounds modify smoothened localization and hedgehog pathway activity

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Highlights? Screened compound libraries for modulation of Smo movement to the primary cilium ? Identified glucocorticoids inducing Smo ciliary accumulation without activation ? They sensitize cells to Hh input and potentially modify the efficacy of Smo antagonists ? Identified a glucocorticoid inhibitor effective in inhibiting drug-resistant Smo mutants     

An Electrophoretic Mobility Shift Assay Identifies a Mechanistically Unique Inhibitor of Protein Sumoylation

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Highlights? Capillary electrophoresis assay using a mobility shift as a readout to study sumoylation ? Assay identified a 2-D08 (2′,3′,4′-trihydroxyflavone) as a potent sumoylation inhibitor ? 2-D08 acts by inhibiting the transfer of SUMO-1 from the E2 thioester to the SUMO substrate ? 2-D08 inhibits sumoylation of topo-I in two different breast cancer cell lines     

Blood Tolerant Laccase by Directed Evolution

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Highlights? A fungal laccase was tailored by directed evolution to be functional in human blood ? The mutant is active at physiological pH and under high concentrations of halides ? Mutations introduced by evolution are located at the surroundings of the T1 copper     

Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition

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Highlights? Synthetically accessible hybrids of 1,25D and HDACi are created ? Hybrids with hydroxamic acids in the A-ring binding pocket are active as VDR agonists ? Hybrids are potent inhibitors of 1,25D-sensitive and 1,25D-resistant cancer cell growth     

Specific Small Molecule Inhibitors of Skp2-Mediated p27 Degradation

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Highlights? In silico screening against a pocket formed by the Skp2-Cks1 protein interface ? Structure-based discovery of Skp2 ligase inhibitors that block p27 ubiquitylation ? Inhibition of Skp2 ligase activity stabilizes p27 protein in melanoma cells ? Inhibitor induction of p27 results in cell cycle arrest in various cancer cells     

HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery

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Highlights? HTS by NMR combines protein NMR and combinatorial chemistry to screen large libraries ? The approach is best suited to identify ligands to protein-protein interactions ? The method enables a rapid assessment of the druggability of a given target ? We applied the method to a test case and to derive potent and selective EphA4 ligands     

Codon Randomization for Rapid Exploration of Chemical Space in Thiopeptide Antibiotic Variants

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Highlights? Thiopeptide GE37468 expression was increased 30-fold above previous reports ? Codon randomization enabled rapid exploration of chemical space ? Thirteen thiopeptide analogs had activity against MRSA ? Identification of linear precursor peptides allowed insights into biosynthetic timing     

A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

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Highlights? S1P₁ antagonists were designed and optimized ? NIBR-0213 is a highly potent and selective S1P₁ antagonist ? NIBR-0213 induces long lasting reduction of lymphocyte counts in blood ? NIBR-0213 has comparable efficacy to fingolimod (FTY720) in a mouse EAE model     

BTZO-1, a cardioprotective agent, reveals that macrophage migration inhibitory factor regulates ARE-mediated gene expression

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Highlights? ARE activation is involved in cellular protection against oxidative stress ? MIF is a ubiquitous protein with conserved nucleophilic Pro1 in a hydrophobic pocket ? BTZO-1 selectively binds to MIF, and its binding required the intact N-terminal Pro1 ? Binding of BTZO-1 to MIF leads to the ARE activation in cardiomyocytes.     

Reconstitution of Nucleosome Demethylation and Catalytic Properties of a Jumonji Histone Demethylase

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Highlights? Catalytic domain of JMJD2A (cJMJD2A) removes methyl marks in a distributive manner ? Homogeneously methylated nucleosomes were used as substrates ? Quantitative assay for nucleosome demethylation has been developed     

Orthogonal Ubiquitin Transfer through Engineered E1-E2 Cascades for Protein Ubiquitination

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Highlights? Orthogonal ubiquitin (UB) transfer pathway to synthesize specific UB-E2 conjugates ? Phage display to engineer UB-E1 and UB-E2 interactions ? Engineered xUB-xE1 and xE1-xE2 pairs with no cross-reactivities with native enzymes     

AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern

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Highlights? AMP-activated protein kinase (AMPK) is a sensor of cellular energy status ? Drugs that activate AMPK have potential in type 2 diabetes and in cancer ? Many existing drugs and xenobiotics (e.g., metformin, salicylate) activate AMPK ? Most, but not all, AMPK-activating xenobiotics inhibit mitochondrial function     

ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species

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Highlights? Zebrafish provide a viable assay for the biological toxicity of 5-nitrofurans ? ALDH2 inhibitors prevent 5-nitrofuran toxicity in zebrafish and yeast ? Genetic dependence on ALDH2 for 5-nitrofuran toxicity in zebrafish and yeast systems ? 5-Nitrofurans bind to and are substrates of human ALDH2     

A LOV2 Domain-Based Optogenetic Tool to Control Protein Degradation and Cellular Function

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Highlights? Optogenetic tool to control the stability of soluble and membrane proteins ? Engineered using the LOV2 domain and a murine ornithine decarboxylase-like degron ? Creation of light-switchable, conditional mutants ? Graded response to very low blue light intensities allows yeast photography     

Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2

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Highlights? CPYPP binds to DOCK2 DHR-2 domain and inhibits its catalytic activity ? CPYPP inhibits DOCK2-mediated Rac activation in cells ? The structural features of CPYPP required for its inhibitory effect were revealed ? CPYPP inhibits lymphocyte migration and activation in vitro and in vivo     

The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2

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Highlights? The natural anticancer compound rocaglamide directly binds to PHB1 and PHB2 ? Rocaglamide blocks PHB-mediated activation of CRaf-MEK-ERK pathway and cancer proliferation ? Rocaglamide may serve as a new type of anticancer agent ? Rocaglamide may serve as a new molecular tool for studying PHB-mediated cellular functions     

A Synthetic Substrate of DNA Polymerase Deviating from the Bases,Sugar, and Leaving Group of Canonical Deoxynucleoside Triphosphates

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Highlights? A highly modified nucleotide as substrate for polymerases ? The reversibility of the polymerase reaction at the template level ? Synthesis of a nucleoside with two anomeric centers     

Insights into a Divergent Phenazine Biosynthetic Pathway Governed by a Plasmid-Born Esmeraldin Gene Cluster

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Highlights? Esm gene cluster resides on a highly unstable giant plasmid ? EsmA1 and A2 work together to promote the formation of phenazine-1,6-dicarboxylic acid ? Polyketide synthase enzymes EsmB1–B5 catalyze the unique methyl transfer ? Atypical polyketide synthase enzymes EsmD1–D3 catalyze the esterification.     

Structural and functional investigation of the intermolecular interaction between NRPS adenylation and carrier protein domains

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Highlights? Crystallographic structure of NRPS adenylation and PCP domain interface ? NRPS adenylation C-terminal domain rotation creates appropriate PCP interface ? Mechanism-based inhibitor traps conformationally flexible proteins ? Structure-guided mutagenesis improves noncognate NRPS interactions     

Development of Antibiotic Activity Profile Screening for the Classification and Discovery of Natural Product Antibiotics

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Highlights? Antibiotics can be classified by structural class based on biological fingerprints ? BioMAP predicts the presence of known compounds in natural product extracts ? BioMAP reveals compounds with unique antibacterial properties ? A naphthoquinone antibiotic with a unique carbon skeleton has been discovered