Engineering the Substrate Specificity of the DhbE Adenylation Domain by Yeast Cell Surface Display

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Highlights? Yeast surface display to engineer substrate recognition of adenylation (A) domains ? Synthesis of bisubstrate inhibitors for yeast selection of A domain library ? Identifying DhbE mutants specific for 3-hydroxybenzoic acid and 2-aminobenzoic acid ? Key residues in A domain for substrate recognition and transfer     

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     

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     

An integrated chemical biology approach provides insight into cdk2 functional redundancy and inhibitor sensitivity

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Highlights? Demonstration that Cdk2 is rate-limiting for DNA replication due to insufficient Cdk1 activity ? A simple bioinformatic approach to design inhibitor resistant mutations in kinases ? Demonstration of distinct binding modes and selectivity of Cdk inhibitors ? Identification of kinetic and structural mechanisms of inhibitor resistance     

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)     

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     

Directed Evolution of a Soluble Human IL-17A Receptor for the Inhibition of Psoriasis Plaque Formation in a Mouse Model

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Highlights? IL-17 is involved in many inflammatory diseases ? Directed evolution of IL-17A receptor results in improved IL-17A affinity ? The engineered receptors efficiently inhibit IL-17A induced cytokine secretion ? Engineered receptor promotes the recovery of psoriasis plaques in mouse model     

Synthesis and Screening of Stereochemically Diverse Combinatorial Libraries of Peptide Tertiary Amides

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Highlights? A convenient synthesis of libraries of conformationally-constrained N-substituted oligoalanines ? A screen of such a library provided much higher affinity hits than a library of peptoids lacking c-alpha substitution ? Analysis of the isolated protein ligands demonstrated that the stereochemistry of the chiral centers was important ? These libraries should be a useful source of high affinity protein ligands     

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     

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.     

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     

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     

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     

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     

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     

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     

A Bacterial Source for Mollusk Pyrone Polyketides

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Highlights? Symbiotic bacteria synthesize compounds found in mollusks ? Physically defended mollusks provide a source for bioactive metabolite discovery ? A type of pyrone polyketide pathway described ? Nocardiopsis strains may be widespread, casually associated symbionts of inveterbrates     

Catalytic contributions of key residues in the adenine glycosylase MutY revealed by pH-dependent kinetics and cellular repair assays

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Highlights? Asp 138 must be deprotonated to stabilize the transition state for maximal activity ? Consequences of altering catalytic amino acids in MutY on cellular mismatch repair ? Correlation of MutY enzymatic parameters with ability to mediate cellular repair ? Importance of high affinity binding of MutY to the OG:A mismatch for high levels of repair     

Firefly luciferase in chemical biology: a compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter

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Highlights? A representative small molecule library contains 12% firefly luciferase inhibitors ? Competitive, noncompetitive, uncompetitive, and MAI inhibitors were identified ? For FLuc-RGAs 65% of FLuc inhibitors with known MOIs increased the luminescence signal ? Methods to identify FLuc inhibitors that interfere with assay results are described     

A fluorogenic red fluorescent protein heterodimer

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Highlights? A dimerization-dependent red fluorescent protein (ddRFP) was engineered ? ddRFP fluorogenesis results from modulation of pK_a and quantum yield ? ddRFP-based biosensors exhibit reversible intensiometric responses ? ddRFP-based biosensors can detect Ca²⁺ dynamics and caspase-3 activity in live cells