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     

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     

Prohibitin Ligands in Cell Death and Survival: Mode of Action and Therapeutic Potential

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Highlights? Prohibitins regulate cell survival, metabolism, and inflammation ? Prohibitins act as a hub for many signaling pathways ? Prohibitin ligands are examined in cancer, Parkinson’s disease, and obesity     

Biomembrane interactions reveal the mechanism of action of surface-immobilized host defense IDR-1010 peptide

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Highlights? Biomembrane interactions of surface-tethered host defense peptides are studied ? Polymer brush-tethered IDR-1010cys showed enhanced biomembrane interactions ? Mechanism of action of surface-tethered peptides is different from its soluble form     

Analysis of Chemical and Biological Features Yields Mechanistic Insights into Drug Side Effects

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Highlights? Biological and chemical traits are flagged in >1,000 drug side effects ? Mechanistic insights are gained for most of the phenotypes ? Chemical features can account for unspecific or intricate biological phenomena ? Blending chemistry and biology helps in anticipating adverse events     

Location Matters: Site of Conjugation Modulates Stability and Pharmacokinetics of Antibody Drug Conjugates

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Highlights? Site-specific conjugation of diverse payloads can be achieved with transglutaminase ? Efficient conjugation was achieved at multiple positions throughout an antibody ? Site of conjugation has significant impact on ADC stability and pharmacokinetics ? Differences in ADC stability and pharmacokinetics are species dependent     

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     

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     

Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface

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Highlights? Inhibitors of pVHL:HIF-1α interaction are ligand-efficient and retain binding mode ? Ro3-compliant fragments of these inhibitors are not hits in biophysical screens ? Successful hit fragments break the Ro3 and target at least two subsites at the PPI ? Integration of GE and GLE analyses provide methodology to probe hot spots at a PPI     

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     

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)     

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     

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     

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     

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     

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     

Synthetic Evolving Systems that Implement a User-Specified Genetic Code of Arbitrary Design

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Highlights? Populations of replicating RNAs were constructed by encoded combinatorial chemistry ? The RNAs evolve based on a heritable genotype and corresponding catalytic phenotype ? Genotype and phenotype are related by a user-specified genetic code ? The evolved enzymes included both highly active catalysts and molecular parasites     

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