Discovery of potent and selective covalent inhibitors of JNK

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Highlights? JNK inhibitors have been designed that target a conserved cysteine residue ? JNK-IN-8 is a highly selective JNK inhibitor based on multiple profiling strategies ? Covalent formation is crucial for both high potency and high specificity ? JNK-IN-8 inhibits c-Jun phosphorylation at submicromolar concentrations in cells     

Biosynthetic Conclusions from the Functional Dissection of Oxygenases for Biosynthesis of Actinorhodin and Related Streptomyces Antibiotics

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Highlights? ActVA-ORF5 is a flavin-dependent monooxygenase required for actinorhodin biosynthesis ? ActVA-ORF5 and its three close homologs were functionally dissected ? ActVA-ORF5 and Gra-21 are bifunctional at C-6/C-8, while Med-7 acts only for C-6 ? AlnT exhibits different regiospecificity for oxidation of tricyclic substrates     

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     

Fluorescence Imaging of Single-Copy DNA Sequences within the Human Genome Using PNA-Directed Padlock Probe Assembly

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Highlights? PNA-directed assembly of the labeling complex on duplex DNA ? Padlock probes combined with rolling circle amplification for signal amplification ? Multitarget visualization within the human genome with high sequence selectivity     

Identification of exosite-targeting inhibitors of anthrax lethal factor by high-throughput screening

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Highlights? Development of an assay for LF protease using a full-length protein substrate ? Lichen depsidones identified as exosite-targeting LF inhibitors ? Exosite inhibitors protect macrophages from LF cytotoxicity     

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     

Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened

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Highlights? New small molecule antagonists of Smo with distinct binding modes discovered from high throughput screens ? ALLO-1 and ALLO-2 are potent against the drug-resistant mutant of Smo ? ALLO-1 is potent against oncogenic mutant of Smo (SmoM2)     

Interplay between the Ribosomal Tunnel,Nascent Chain,and Macrolides Influences Drug Inhibition

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Highlights? Macrolides exhibit nascent polypeptide chain–dependent inhibition ? Peptides can form specific interactions with the ribosomal tunnel ? A covalent bond between tylosin and the ribosome is necessary for inhibitory activity     

Morphobase,an Encyclopedic Cell Morphology Database,and Its Use for Drug Target Identification

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Highlights? Development of an encyclopedia of cell morphology, Morphobase ? Small molecules classified by mode of action with Morphobase ? Morphobase system rapidly predicts molecular targets of compounds ? NPD6689 targets tubulin and is a lead for a class of antitubulin drugs     

Picoliter cell lysate assays in microfluidic droplet compartments for directed enzyme evolution

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Highlights? Microfluidic droplet compartments miniaturize cell lysate screening assays ? Picoliter single-cell lysate assays comparable in sensitivity to macroscale ? Directed evolution results in improved clones validating this experimental set-up ? Precision of droplet sorting enables enrichment of clones with slight improvements     

Structural Properties of Model Phosphatidylcholine Flippases

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Highlights? Model peptides induce sequence-dependent flip of lipids with different headgroups ? Flip activity of peptides depends on the lipid composition of the host membrane ? SNARE proteins have lipid flippase activity     

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     

Flux through Trehalose Synthase Flows from Trehalose to the Alpha Anomer of Maltose in Mycobacteria

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Highlights? Flux through trehalose synthase (TreS) in mycobacteria is from trehalose to maltose ? The appropriate α anomer is formed by TreS for maltose kinase of the GlgE pathway ? The specificity of TreS for α-maltose is retained with deoxyfluoro analogs ? TreS supports cytosolic/capsular α-glucan but not trehalose mycolate biosynthesis     

Chemical Proteomics with Sulfonyl Fluoride Probes Reveals Selective Labeling of Functional Tyrosines in Glutathione Transferases

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Highlights? Sulfonyl fluoride probes label diverse GSTs in both plant and mouse proteomes ? GSTs are labeled on Tyr residues in unconserved substrate binding pockets ? Labeled Tyr residues are essential for GST function     

CXCR4 Stimulates Macropinocytosis: Implications for Cellular Uptake of Arginine-Rich Cell-Penetrating Peptides and HIV

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Highlights? CXCR4 was identified as a receptor to stimulate cellular uptake of R12 peptide ? Interaction with R12 stimulates internalization of CXCR4 via macropinocytosis ? SDF-1α and HIV-1 gp120 protein also induce macropinocytosis ? Macropinocytic uptake of HIV-1 diminished the infection of host cells     

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     

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     

Indirubin Derivatives Modulate TGFβ/BMP Signaling at Different Levels and Trigger Ubiquitin-Mediated Depletion of Nonactivated R-Smads

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Highlights? Inhibition of TGFβ/BMP signaling by degradation of nonactivated R-Smads ? Total R-Smad pools are regulated through the ubiquitin-proteasome pathway ? Ubiquitin proteases USP9x and USP34 interact directly with R-Smads ? Indirubin derivative E738 controls BMP/TGFβ signaling though R-Smad depletion     

Terpendole E,a Kinesin Eg5 Inhibitor,Is a Key Biosynthetic Intermediate of Indole-Diterpenes in the Producing Fungus Chaunopycnis alba

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Highlights? The terpendole biosynthetic gene cluster was isolated ? Terpendole E is a key biosynthetic intermediate of indole-diterpenes ? Terpendole E was overproduced by gene knockout of the bispecific enzyme TerP ? Indole-diterpene biosynthetic pathways can be classified into two groups