Search our Database of Scientific Publications and Authors

I’m looking for a

    2919 results match your criteria ACS Chemical Biology [Journal]

    1 OF 59

    Screening a protein array with synthetic biotinylated inorganic polyphosphate to define the human polyP-ome.
    ACS Chem Biol 2018 Jun 20. Epub 2018 Jun 20.
    Phenotypes are established by thigh regulation on protein functions. This regulation can be mediated allosterically, through protein binding, and covalently, through post-translational modification (PTM). The integration of an ever-increasing number of PTMs into regulatory networks enable and define the proteome complexity. Read More

    Enzyme-Activated Fluorogenic Probes for Live-Cell and in Vivo Imaging.
    ACS Chem Biol 2018 Jun 20. Epub 2018 Jun 20.
    Fluorogenic probes, small-molecule sensors that unmask brilliant fluorescence upon exposure to specific stimuli, are powerful tools for chemical biology. Those probes that respond to enzymatic activity illuminate the complex dynamics of biological processes at a level of spatiotemporal detail and sensitivity unmatched by other techniques. Here, we review recent advances in enzyme-activated fluorogenic probes for biological imaging. Read More

    An Assembly-activating Site in the Hepatitis B Virus Capsid Protein can also Trigger Disassembly.
    ACS Chem Biol 2018 Jun 19. Epub 2018 Jun 19.
    The Hepatitis B Virus (HBV) core protein homodimers self-assemble to form an icosahedral capsid that packages the viral genome. Disassembly occurs in the nuclear basket to release the mature genome to the nucleus. Small molecules have been developed that bind to a pocket at the inter-dimer interface to accelerate assembly and strengthen interactions between subunits; these are under development as antiviral agents. Read More

    Generation of potent anti-HER1/2 immunotoxins by protein ligation using split inteins.
    ACS Chem Biol 2018 Jun 19. Epub 2018 Jun 19.
    Cell targeting protein toxins have gained increasing interest for cancer therapy, aimed at increasing the therapeutic window and to reduce systemic toxicity. Since recombinant expression of immunotoxins consisting of a receptor-binding and a cell-killing moiety is hampered by their high toxicity in an eukaryotic production host, most applications rely on recombinant production of fusion proteins consisting of an antibody fragment and a protein toxin in bacterial hosts such as Escherichia coli (E. coli). Read More

    Augmenting vaccine immunogenicity through the use of natural human anti-rhamnose antibodies.
    ACS Chem Biol 2018 Jun 19. Epub 2018 Jun 19.
    Utilizing natural antibodies to augment vaccine immunogenicity is a promising approach towards cancer immunotherapy. Anti-rhamnose (anti-Rha) antibodies are some of the most common natural anti-carbohydrate antibodies present in human serum. Therefore, rhamnose can be utilized as a targeting moiety for a rhamnose-containing vaccine to prepare an effective vaccine formulation. Read More

    Probing the flexibility of an iterative modular polyketide synthase with non-native substrates in vitro.
    ACS Chem Biol 2018 Jun 18. Epub 2018 Jun 18.
    In the search for molecular machinery for custom biosynthesis of valuable compounds, the modular Type I polyketide synthases (PKSs) offer great potential. In this study we investigate the flexibility of BorM5, the iterative fifth module of the borrelidin synthase, with a panel of non-native priming substrates in vitro. BorM5 differentially extends various aliphatic and substituted substrates. Read More

    Optical Recording of Zn Dynamics in the Mitochondrial Matrix and Intermembrane Space with the GZnP2 Sensor.
    ACS Chem Biol 2018 Jun 18. Epub 2018 Jun 18.
    The zinc ion (Zn2+) is emerging as an important signaling molecule. Here we engineered an improved Zn2+ probe GZnP2 based on a previously developed fluorescent sensor GZnP1 to provide a higher fluorescent readout (2-fold higher) that is proportional to cellular labile Zn2+ concentrations. We further developed a set of GZnP2 derived imaging tools to determine the labile Zn2+ concentrations in the mitochondrial matrix, mitochondrial intermembrane space (IMS) and cytosol in four different cell lines (HeLa, Cos-7, HEK293 and INS-1). Read More

    LOV Domains in the Design of Photoresponsive Enzymes.
    ACS Chem Biol 2018 Jun 15. Epub 2018 Jun 15.
    In nature, a multitude of mechanisms have emerged for regulating biological processes and, specifically, protein activity. Light as a natural regulatory element is of outstanding interest for studying and modulating protein activity because it can be precisely applied with regard to a site of action, instant of time, or intensity. Naturally occuring photoresponsive proteins, predominantly those containing a light-oxygen-voltage (LOV) domain, have been characterized structurally and mechanistically and also conjugated to various proteins of interest. Read More

    Identification of Compounds That Decrease Glioblastoma Growth and Glucose Uptake in Vitro.
    ACS Chem Biol 2018 Jun 15. Epub 2018 Jun 15.
    Department of Cell, Developmental and Integrative Biology , University of Alabama at Birmingham , Birmingham , Alabama , United States.
    Tumor heterogeneity has hampered the development of novel effective therapeutic options for aggressive cancers, including the deadly primary adult brain tumor glioblastoma (GBM). Intratumoral heterogeneity is partially attributed to the tumor initiating cell (TIC) subset that contains highly tumorigenic, stem-like cells. TICs display metabolic plasticity but can have a reliance on aerobic glycolysis. Read More

    Biosynthesis, Synthesis and Activities of Barnesin A, a NRPS-PKS Hybrid Produced by an Anaerobic Epsilonproteobacterium.
    ACS Chem Biol 2018 Jun 14. Epub 2018 Jun 14.
    Despite the wealth of physiological knowledge and plentiful genomes available, only few natural products of anaerobic bacteria have been identified until today and even less have been linked to their biosynthetic gene cluster. Here, we analyzed a unique NRPS-PKS hybrid gene cluster from an anaerobic Epsilonproteobacterium (Sulfurospirillum barnesii). Phylogenetic analysis of key biosynthetic genes, gene expression studies and comparative metabolomics resulted in the identification of the first anoxically biosynthesized NRPS-PKS hybrid metabolite, a lipo-dipeptide with a vinylogous side chain, named barnesin A. Read More

    Small molecule inhibitors of NFkB reverse iron overload and hepcidin deregulation in a zebrafish model for Hereditary Hemochromatosis Type 3.
    ACS Chem Biol 2018 Jun 13. Epub 2018 Jun 13.
    Hereditary hemochromatosis (HH) is one of the most common genetic disorders in Caucasian populations, with no viable therapeutic options except phlebotomy. We describe a zebrafish model of human HH (HH) created by targeted mutagenesis of the gene encoding Transferrin receptor 2 (tfr2). TFR2 mutations in humans lead to HH Type 3, a rare but severe form of the disease. Read More

    Structure-based design, synthesis and characterization of the first irreversible inhibitor of Focal Adhesion Kinase.
    ACS Chem Biol 2018 Jun 13. Epub 2018 Jun 13.
    Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Read More

    Chemoenzymatic Synthesis of N-glycan Positional Isomers and Evidence for Branch Selective Binding by Monoclonal Antibodies and Human C-type Lectin Receptors.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    Here we describe a strategy for the rapid preparation of pure positional isomers of complex N-glycans to complement an existing array comprising a larger number of N-glycans and smaller glycan structures. The expanded array was then employed to study context-dependent binding of structural glycan fragments by monoclonal antibodies and C-type lectins. A partial enzymatic elongation of semi-protected core structures was combined with the protecting group aided separation of positional isomers by preparative HPLC. Read More

    Engineering Heterodimeric Kinesins through Genetic Incorporation of Noncanonical Amino Acids.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    Department of Biochemistry and Biophysics , Oregon State University , Corvallis , Oregon 97331 , United States.
    Kinesins are commonly homodimers with two identical heavy chains (protomers) and play indispensable roles in many intracellular processes. Engineered heterodimeric kinesins with two distinct protomers are important tools for dissecting coordination and regulation of naturally occurring kinesin homodimers. Here, we report a chemical-biology-based approach that generates kinesin heterodimers by combining genetic incorporation of reactive noncanonical amino acids and small-molecule-based cross-linking. Read More

    Precursor-based selective methyl labelling of cell-free synthesized proteins.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    NMR studies of large proteins are complicated by pronounced spectral overlap and large line width. Re-ducing complexity by [13C, 1H] selective labelling of L-Val, L-Leu and/or L-Ile residues in combination with optional perdeuteration is therefore commonly approached by supplying labelled amino acid precursors into bacterial expression cultures, although often compromised by high label costs, precursor instability and label scrambling. Cell-free expres-sion combines efficient production of membrane proteins with significant advantages for protein labelling such as small reaction volumes, defined amino acid pools, and reliable label incorporation. Read More

    Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD.
    ACS Chem Biol 2018 Jun 19. Epub 2018 Jun 19.
    Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America.
    Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Read More

    The Biochemical Basis of Vitamin A Production from the Asymmetric Carotenoid β-Cryptoxanthin.
    ACS Chem Biol 2018 Jun 15. Epub 2018 Jun 15.
    Department of Pharmacology , Case Western Reserve University School of Medicine , Cleveland , Ohio 44106 , United States.
    Vitamin A serves essential functions in mammalian biology as a signaling molecule and chromophore. This lipid can be synthesized from more than 50 putative dietary provitamin A precursor molecules which contain at least one unsubstituted β-ionone ring. We here scrutinized the enzymatic properties and substrate specificities of the two structurally related carotenoid cleavage dioxygenases (CCDs) which catalyze this synthesis. Read More

    Lawsone, Juglone, and β-Lapachone Derivatives with Enhanced Mitochondrial-Based Toxicity.
    ACS Chem Biol 2018 Jun 15. Epub 2018 Jun 15.
    Unidad de Investigación , Hospital Universitario Nuestra Señora de La Candelaria , 38010 Tenerife , Spain.
    Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS), and inhibition of proteins. Here, we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone, and β-lapachone. Read More

    Direct Genetic and Enzymatic Evidence for Oxidative Cyclization in Hygromycin B Biosynthesis.
    ACS Chem Biol 2018 Jun 19. Epub 2018 Jun 19.
    Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University) , Ministry of Education and Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , People's Republic of China.
    Hygromycin B is an aminoglycoside antibiotic with a structurally distinctive orthoester linkage. Despite its long history of use in industry and in the laboratory, its biosynthesis remains poorly understood. We show here, by in-frame gene deletion in vivo and detailed enzyme characterization in vitro, that formation of the unique orthoester moiety is catalyzed by the α-ketoglutarate- and non-heme iron-dependent oxygenase HygX. Read More

    High Throughput Screens to Identify Autophagy Inducers that Function by Disrupting Beclin 1/Bcl-2 Binding.
    ACS Chem Biol 2018 Jun 7. Epub 2018 Jun 7.
    Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. We sought to establish a method for developing new chemical compounds that specifically induce autophagy. Read More

    Role of Gln222 in Photoswitching of Aequorea Fluorescent Proteins: A Twisting and H-Bonding Affair?
    ACS Chem Biol 2018 Jun 19. Epub 2018 Jun 19.
    NEST , Scuola Normale Superiore and NANO-CNR , 56127 Pisa , Italy.
    Reversibly photoswitchable fluorescent proteins (RSFPs) admirably combine the genetic encoding of fluorescence with the ability to repeatedly toggle between a bright and dark state, adding a new temporal dimension to the fluorescence signal. Accordingly, in recent years RSFPs have paved the way to novel applications in cell imaging that rely on their reversible photoswitching, including many super-resolution techniques such as F-PALM, RESOLFT, and SOFI that provide nanoscale pictures of the living matter. Yet many RSFPs have been engineered by a rational approach only to a limited extent, in the absence of clear structure-property relationships that in most cases make anecdotic the emergence of the photoswitching. Read More

    Diatom allantoin synthase provides structural insights into natural fusion protein therapeutics.
    ACS Chem Biol 2018 Jun 6. Epub 2018 Jun 6.
    Humans have lost the ability to convert urate into the more soluble allantoin with the evolutionary inactivation of three enzymes of the uricolytic pathway. Restoration of this function through enzyme replacement therapy can treat severe hyperuricemia and Lesch-Nyhan disease. Through a genomic exploration of natural gene fusions, we found that plants and diatoms independently evolved a fusion protein (allantoin synthase) complementing two human pseudogenes. Read More

    The Role of Reactive Oxygen Species and Ferroptosis in Heme-Mediated Activation of Human Platelets.
    ACS Chem Biol 2018 Jun 13. Epub 2018 Jun 13.
    Department of Inorganic and Physical Chemistry , Indian Institute of Science , Bangalore 560 012 , India.
    Hemolysis, a process by which the destruction of red blood cells leads to the release of hemoglobin, is a critical event observed during hemolytic disorders. Under oxidative stress conditions, hemoglobin can release its heme prosthetic group, which is highly cytotoxic and can catalyze the generation of reactive oxygen species (ROS), leading to several undesired redox reactions in the cells. Herein, we demonstrate for the first time that heme can mediate the activation and death of human platelets through ferroptosis, which is an iron-dependent form of nonapoptotic cell death. Read More

    Development of Photoaffinity Probe for the Discovery of Steviol Glycosides Biosynthesis Pathway in Stevia rebuadiana and Rapid Substrate Screening.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology , Chinese Academy of Sciences , Shanghai 200032 , China.
    Functional discovery and characterization of the target enzymes responsible for the biosynthesis pathway coded for the genes is ongoing, and the unknown functional diversity of this class of enzymes has been revealed by genome sequencing. Commonly, it is feasible in annotating of biosynthetic genes of prokaryotes due to the existence of gene clusters of secondary metabolites. However, in eukaryotes, the biosynthetic genes are not compactly clustered in the way of prokaryotes. Read More

    Surface-Modified Macrophages Facilitate Tracking of Breast Cancer-Immune Interactions.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    Department of Chemistry , University of Massachusetts , 710 North Pleasant Street , Amherst , Massachusetts 01003 , United States.
    The immune system has been found to play key roles in cancer development and progression. Macrophages are typically considered to be pro-inflammatory cells but can also facilitate pro-oncogenic activities via associations with tumors and metastases. The study of macrophages and their interactions within the context of cancer microenvironments is stymied by the lack of a system to track them. Read More

    Subcellular Protein Labeling by a Spatially Restricted Arylamine N-Acetyltransferase.
    ACS Chem Biol 2018 Jun 14. Epub 2018 Jun 14.
    Department of Biomolecular Chemistry, Institute of Molecules and Materials , Radboud University , Nijmegen , Heyendaalseweg 135 , 6525 AJ , The Netherlands.
    Mapping proteins at a specific subcellular location is essential to gaining detailed insight on local protein dynamics. We have developed an enzymatic strategy to label proteins on a subcellular level using arylamine N-acetyltransferase (NAT). The NAT enzyme activates an arylhydroxamic acid functionality into a nitrenium ion that reacts fast, covalently, and under neutral conditions with nucleophilic residues of neighboring proteins. Read More

    Detection of Chemical Engagement of Solute Carrier Proteins by a Cellular Thermal Shift Assay.
    ACS Chem Biol 2018 Jun 6;13(6):1480-1486. Epub 2018 Jun 6.
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences , 1090 Vienna , Austria.
    Solute carriers (SLCs) are transmembrane proteins that transport various nutrients, metabolites, and drugs across cellular membranes. Despite the relevance of SLCs to cell homeostasis, metabolism, and disease states, for the majority of SLCs we lack experimental evidence regarding the nature of the cognate ligands, whether endobiotic or xenobiotic. Moreover, even for the roughly 20 SLCs for which inhibitors have been characterized, engagement assays in cells are limited to the accessibility of radiolabeled or fluorescent probes. Read More

    NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening.
    ACS Chem Biol 2018 Jun 13. Epub 2018 Jun 13.
    Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis , National Cancer Institute , Frederick , Maryland 21702-1201 , United States.
    The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. Read More

    HaloTag Assay Suggests Common Mechanism of E. coli Membrane Permeabilization Induced by Cationic Peptides.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    Department of Chemistry and Molecular Biophysics Program University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.
    Permeabilization of the Gram-negative bacterial outer membrane (OM) by antimicrobial peptides (AMPs) is the initial step enabling access of the AMP to the cytoplasmic membrane. We present a new single-cell, time-resolved fluorescence microscopy assay that reports on the permeabilization of the E. coli OM to small molecules with a time resolution of 3 s or better. Read More

    Effect of Noncanonical Amino Acids on Protein-Carbohydrate Interactions: Structure, Dynamics, and Carbohydrate Affinity of a Lectin Engineered with Fluorinated Tryptophan Analogs.
    ACS Chem Biol 2018 Jun 12. Epub 2018 Jun 12.
    Austrian Centre of Industrial Biotechnology , Petersgasse 14 , 8010 Graz , Austria.
    Protein-carbohydrate interactions play crucial roles in biology. Understanding and modifying these interactions is of major interest for fighting many diseases. We took a synthetic biology approach and incorporated noncanonical amino acids into a bacterial lectin to modulate its interactions with carbohydrates. Read More

    Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein.
    ACS Chem Biol 2018 Jun 29;13(6):1499-1505. Epub 2018 May 29.
    Harry Perkins Institute of Medical Research and Centre for Medical Research , The University of Western Australia , Nedlands 6009 , Australia.
    It has been widely shown that ligand-binding residues, by virtue of their orientation, charge, and solvent exposure, often have a net destabilizing effect on proteins that is offset by stability conferring residues elsewhere in the protein. This structure-function trade-off can constrain possible adaptive evolutionary changes of function and may hamper protein engineering efforts to design proteins with new functions. Here, we present evidence from a large randomized mutant library screen that, in the case of PUF RNA-binding proteins, this structural relationship may be inverted and that active-site mutations that increase protein activity are also able to compensate for impaired stability. Read More

    Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry.
    ACS Chem Biol 2018 Jun 11. Epub 2018 Jun 11.
    Department of Life, Health and Environmental Sciences , University of L'Aquila , 67100 L'Aquila , Italy.
    Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off-target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Read More

    Characterization of the Lysine Acylomes and the Substrates Regulated by Protein Acyltransferase in Mycobacterium smegmatis.
    ACS Chem Biol 2018 Jun 5;13(6):1588-1597. Epub 2018 Jun 5.
    Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering , East China University of Science and Technology , Shanghai 200237 , China.
    Protein acylation plays important roles in bacterial pathogenesis through regulation of enzymatic activity, protein stability, nucleic acid binding ability, and protein-protein interactions. Mycobacteria, a genus including invasive pathogens known to cause serious diseases, shapes its pathogenicity through adaptation of its energy metabolism to microenvironments encountered within mammalian hosts. In this process, acetyl-CoA and propionyl-CoA function as important intermediates. Read More

    Partial Intrinsic Disorder Governs the Dengue Capsid Protein Conformational Ensemble.
    ACS Chem Biol 2018 Jun 5;13(6):1621-1630. Epub 2018 Jun 5.
    Bioinformatics institute (BII) , Agency for Science, Technology and Research (A*STAR) , #07-01 Matrix, 30 Biopolis Street , Singapore 138671.
    The 11 kDa, positively charged dengue capsid protein (C protein) exists stably as a homodimer and colocalizes with the viral genome within mature viral particles. Its core is composed of four alpha helices encompassing a small hydrophobic patch that may interact with lipids, but approximately 20% of the protein at the N-terminus is intrinsically disordered, making it challenging to elucidate its conformational landscape. Here, we combine small-angle X-ray scattering (SAXS), amide hydrogen-deuterium exchange mass spectrometry (HDXMS), and atomic-resolution molecular dynamics (MD) simulations to probe the dynamics of dengue C proteins. Read More

    The Chemoattractant Glorin Is Inactivated by Ester Cleavage during Early Multicellular Development of Polysphondylium pallidum.
    ACS Chem Biol 2018 Jun 24;13(6):1506-1513. Epub 2018 May 24.
    Pharmaceutical Biology, Institute of Pharmacy , Friedrich Schiller University , Jena , Germany.
    Among the amoebozoan species capable of forming fruiting bodies, the dictyostelid social amoebae stand out since they form true multicellular organisms by means of single cell aggregation. Upon food depletion, cells migrate across gradients of extracellular signals initiated by cells in aggregation centers. The model species that is widely used to study multicellular development of social amoebae, Dictyostelium discoideum, uses cyclic adenosine monophosphate (cAMP) as a chemoattractant to coordinate aggregation. Read More

    Biomarker-Based Metabolic Labeling for Redirected and Enhanced Immune Response.
    ACS Chem Biol 2018 Jun 1;13(6):1686-1694. Epub 2018 Jun 1.
    Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States.
    Installation of an antibody-recruiting moiety on the surface of disease-relevant cells can lead to the selective destruction of targets by the immune system. Such an approach can be an alternative strategy to traditional chemotherapeutics in cancer therapy and possibly other diseases. Herein we describe the development of a new strategy to selectively label targets with an antibody-recruiting moiety through its covalent and stable installation, complementing existing methods of employing reversible binding. Read More

    Sensing DNA through DNA Charge Transport.
    ACS Chem Biol 2018 Jun 1. Epub 2018 Jun 1.
    Division of Chemistry and Chemical Engineering , California Institute of Technology , Pasadena , California 91125 , United States.
    DNA charge transport chemistry involves the migration of charge over long molecular distances through the aromatic base pair stack within the DNA helix. This migration depends upon the intimate coupling of bases stacked one with another, and hence any perturbation in that stacking, through base modifications or protein binding, can be sensed electrically. In this review, we describe the many ways DNA charge transport chemistry has been utilized to sense changes in DNA, including the presence of lesions, mismatches, DNA-binding proteins, protein activity, and even reactions under weak magnetic fields. Read More

    Unfolding the Mysteries of Protein Metamorphosis.
    ACS Chem Biol 2018 Jun 7;13(6):1438-1446. Epub 2018 Jun 7.
    Department of Biochemistry , Medical College of Wisconsin , Milwaukee , Wisconsin 53226 , United States.
    Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance and complexity. Intrinsically disordered proteins, chameleonic sequences, morpheeins, and metamorphic proteins have broadened the protein folding paradigm. Here, we discuss noncanonical protein folding patterns, with an emphasis on metamorphic proteins, and we review known metamorphic proteins that occur naturally and that have been engineered in the laboratory. Read More

    The Nitro Group as a Masked Electrophile in Covalent Enzyme Inhibition.
    ACS Chem Biol 2018 Jun 23;13(6):1470-1473. Epub 2018 May 23.
    Department of Chemistry , University at Buffalo , Buffalo , New York 14260-3000 , United States.
    We report the unprecedented reaction between a nitroalkane and an active-site cysteine residue to yield a thiohydroximate adduct. Structural and kinetic evidence suggests the nitro group is activated by conversion to its nitronic acid tautomer within the active site. The nitro group, therefore, shows promise as a masked electrophile in the design of covalent inhibitors targeting binding pockets with appropriately placed cysteine and general acid residues. Read More

    Antitumor Humoral and T Cell Responses by Mucin-1 Conjugates of Bacteriophage Qβ in Wild-type Mice.
    ACS Chem Biol 2018 Jun 30;13(6):1668-1676. Epub 2018 May 30.
    Department of Chemistry and The Skaggs Institute for Chemical Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.
    Mucin-1 (MUC1) is one of the top ranked tumor associated antigens. In order to generate effective anti-MUC1 immune responses as potential anticancer vaccines, MUC1 peptides and glycopeptides have been covalently conjugated to bacteriophage Qβ. Immunization of mice with these constructs led to highly potent antibody responses with IgG titers over one million, which are among the highest anti-MUC1 IgG titers reported to date. Read More

    Fluorescent Labeling of the Nuclear Envelope by Localizing Green Fluorescent Protein on the Inner Nuclear Membrane.
    ACS Chem Biol 2018 Jun 24;13(6):1463-1469. Epub 2018 May 24.
    Department of Bioscience and Bioinformatics , Kyushu Institute of Technology , 680-4 Kawazu , Iizuka 820-8502 , Japan.
    The nuclear envelope (NE) is a double membrane that segregates nuclear components from the cytoplasm in eukaryotic cells. It is well-known that the NE undergoes a breakdown and reformation during mitosis in animal cells. However, the detailed mechanisms of the NE dynamics are not yet fully understood. Read More

    The Role of ClpP Protease in Bacterial Pathogenesis and Human Diseases.
    ACS Chem Biol 2018 Jun 1;13(6):1413-1425. Epub 2018 Jun 1.
    Department of Biochemistry , University of Toronto , Toronto , Ontario M5G 1M1 , Canada.
    In prokaryotic cells and eukaryotic organelles, the ClpP protease plays an important role in proteostasis. The disruption of the ClpP function has been shown to influence the infectivity and virulence of a number of bacterial pathogens. More recently, ClpP has been found to be involved in various forms of carcinomas and in Perrault syndrome, which is an inherited condition characterized by hearing loss in males and females and by ovarian abnormalities in females. Read More

    Different Benzodiazepines Bind with Distinct Binding Modes to GABA Receptors.
    ACS Chem Biol 2018 May 16. Epub 2018 May 16.
    Benzodiazepines are clinically relevant drugs, which bind to GABA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high affinity site at GABA receptors is controversially debated in the literature and in silico studies led to discrepant binding mode hypotheses. In the current study computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABA receptors (position 3 of the 7-membered diazepine ring), could possibly provide experimental evidence in favor of or against the so far proposed binding modes. Read More

    Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo.
    ACS Chem Biol 2018 Jun 30;13(6):1551-1559. Epub 2018 May 30.
    Department of Microbiology and Molecular Genetics , University of Pittsburgh School of Medicine , Pittsburgh , Pennsylvania , United States.
    Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults and is often associated with constitutive tyrosine kinase signaling. These pathways involve the nonreceptor tyrosine kinases Fes, Syk, and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. Read More

    Self-Resistance of Natural Product Producers: Past, Present, and Future Focusing on Self-Resistant Protein Variants.
    ACS Chem Biol 2018 Jun 30;13(6):1426-1437. Epub 2018 May 30.
    Department of Pharmaceutical Sciences , Oregon State University , Corvallis , Oregon 97331 , United States.
    Nature is a prolific producers of bioactive natural products with an array of biological activities and impact on human and animal health. But with great power comes great responsibility, and the organisms that produce a bioactive compound must be resistant to its biological effects to survive during production/accumulation. Microorganisms, particularly bacteria, have developed different strategies to prevent self-toxicity. Read More

    Biosynthesis of Eupatolide-A Metabolic Route for Sesquiterpene Lactone Formation Involving the P450 Enzyme CYP71DD6.
    ACS Chem Biol 2018 Jun 21;13(6):1536-1543. Epub 2018 May 21.
    Institute of Botany , University of Hohenheim , Garbenstraße 30 , 70599 Stuttgart , Germany.
    Sesquiterpene lactones are a class of natural compounds well-known for their bioactivity and are characteristic for the Asteraceae family. Most sesquiterpene lactones are considered derivatives of germacrene A acid (GAA). GAA can be stereospecifically hydroxylated by the cytochrome P450 enzymes (CYP) Lactuca sativa costunolide synthase CYP71BL2 (LsCOS) and Helianthus annuus GAA 8β-hydroxylase CYP71BL1 (HaG8H) at C6 (in α-orientation) or C8 (in β-orientation), respectively. Read More

    Monobody-Mediated Alteration of Lipase Substrate Specificity.
    ACS Chem Biol 2018 Jun 18;13(6):1487-1492. Epub 2018 May 18.
    Department of Biochemistry and Molecular Biology , The University of Chicago , Chicago , Illinois 60637 , United States.
    Controlling the catalytic properties of enzymes remain an important challenge in chemistry and biotechnology. We have recently established a strategy for altering enzyme specificity in which the addition of proxy monobodies, synthetic binding proteins, modulates the specificity of an otherwise unmodified enzyme. Here, in order to examine its broader applicability, we employed the strategy on Candida rugosa lipase 1 (CRL1), an enzyme with a tunnel-like substrate binding site. Read More

    Structural Basis for Natural Product Selection and Export by Bacterial ABC Transporters.
    ACS Chem Biol 2018 Jun 18;13(6):1598-1609. Epub 2018 May 18.
    Department of Life Sciences , Imperial College London , South Kensington, London SW7 2AZ , United Kingdom.
    Bacteria under stress produce ribosomally synthesized and post-translationally modified peptides (RiPPs) to target closely related species, such as the lasso peptide microcin J25 (MccJ25). These peptides are also toxic to the producing organisms that utilize dedicated ABC transporters to achieve self-immunity. MccJ25 is exported by the Escherichia coli ABC transporter McjD through a complex mechanism of recognition that has remained elusive. Read More

    A Symmetric Molecule Produced by Mycobacteria Generates Cell-Length Asymmetry during Cell-Division and Thereby Cell-Length Heterogeneity.
    ACS Chem Biol 2018 Jun 18;13(6):1447-1454. Epub 2018 May 18.
    Department of Microbiology and Cell Biology , Indian Institute of Science , Bengaluru , Karnataka , India.
    Diadenosine polyphosphates, ApA, which contain two adenosines in a 5',5' linkage through phosphodiester bonds involving 2-7 phosphates, regulate diverse cellular functions in all organisms, from bacteria to humans, under normal and stress conditions. We had earlier reported consistent occurrence of asymmetric constriction during division (ACD) in 20-30% of dividing mycobacterial cells in culture, irrespective of different growth media, implying exogenous action of some factor of mycobacterial origin. Consistent with this premise, concentrated culture supernatant (CCS), but not the equivalent volume-wise concentrated unused medium, dramatically enhanced the ACD proportion to 70-90%. Read More

    1 OF 59