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     

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     

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     

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     

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     

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     

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     

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     

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)     

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     

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     

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     

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     

Free Glycine Accelerates the Autoproteolytic Activation of Human Asparaginase

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Highlights? Increased expression of hASNase3 was observed in several tumors, but the relevance is unclear ? Cancer cells have increased glycolytic flux and thus have more glycine but less aspartate ? Glycine activates the asparaginase activity of hASNase3 by promoting self-cleavage ? Thus, glycine may act as a sensor that regulates cellular aspartate concentrations     

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     

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.     

Discovery of Oxysterol-Derived Pharmacological Chaperones for NPC1: Implication for the Existence of Second Sterol-Binding Site

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Highlights? Niemann-Pick disease type C is caused by folding defect in NPC1 protein ? Oxysterols and chemically optimized derivatives act as pharmacological chaperones ? Defects in localization, stability, maturation, and function were corrected in cell ? These derivatives bind to second sterol-binding site on NPC1 protein     

Identification of JadG as the B Ring Opening Oxygenase Catalyzing the Oxidative C-C Bond Cleavage Reaction in Jadomycin Biosynthesis

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Highlights? JadG catalyzes the oxidative C-C bond B ring cleavage of dehydrorabelomycin ? JadG needs FMNH₂ or FADH₂ as cofactors ? JadY is a flavin reductase that could supply FMNH₂ or FADH₂ for JadG     

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