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ACS Chemical Biology

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https://www.readbyqxmd.com/read/30016589/antibody-fucosylation-lowers-fc%C3%AE-riiia-cd16a-affinity-by-limiting-the-conformations-sampled-by-the-n162-glycan
#1
Daniel J Falconer, Ganesh P Subedi, Aaron M Marcella, Adam W Barb
Therapeutic monoclonal antibodies (mAbs) are largely based on the immunoglobulin G1 (IgG1) scaffold and many elicit a cytotoxic cell-mediated response by binding Fc γ receptors. Core fucosylation, a prevalent modification to the asparagine(N)-linked carbohydrate on the IgG1 crystallizable fragment (Fc), reduces Fc γ receptor IIIa (CD16a) binding affinity and mAb efficacy. We determined IgG1 Fc fucosylation reduced CD16a affinity by 1.7 ± 0.1 kcal/mol when compared to afucosylated IgG1 Fc, however, CD16a N-glycan truncation decreased this penalty by 1...
July 17, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30015474/structural-basis-for-binding-of-fluorescent-cmp-neu5ac-mimetics-to-enzymes-of-the-human-st8sia-family
#2
Gesa Volkers, Christian Lizak, Jürgen Niesser, Frederico I Rosell, Johannes Preidl, Vinayaga S Gnanapragassam, Ruediger Horstkorte, Jörg Rademann, Natalie C J Strynadka
Polysialyltransferases synthesize polysialic acid on cell surface-expressed glycoconjugates, which is crucial for developing processes and signaling pathways in eukaryotes. Recent advances in cancer research have rendered polysialyltransferases important drug targets because polysialic acid contributes to cancer cell progression, metastasis and treatment of resistant tumors. To aid the development of high-throughput screening assays for polysialyltransferase inhibitors, we demonstrate that a previously developed class of fluorescent CMP-sialic acid mimetics for sialyltransferases has sub-nanomolar affinities for oligo- and polysialyltransferases and can be used for the rapid screening of new polysialyltransferase inhibitors...
July 17, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30011180/a-chemical-probe-to-monitor-the-parkinsonism-associated-protein-dj-1-in-live-cells
#3
Jonas Drechsel, Franziska A Mandl, Stephan A Sieber
Reactive oxygen species (ROS) play an important role in the onset of Parkinson`s disease (PD) and deciphering protective mechanisms is a major goal for therapeutic development. Here, DJ-1 (PARK7) gained major attention when a conserved cysteine residue with a putative role in oxidative stress sensing/protection was linked to PD. Inspired by previous studies with a bacterial homolog of DJ-1 several amino-epoxycylcohexenones were screened for enzyme inhibition and a chemical probe with specificity for the human ortholog was selected for cellular studies...
July 16, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30010316/-one-pot-two-step-metabolic-labeling-of-teichoic-acids-and-direct-labeling-of-peptidoglycan-reveals-the-tight-coordination-of-both-polymers-insertion-in-pneumococcus-cell-wall
#4
Julie Bonnet, Yung-Sing Wong, Thierry Vernet, Anne Marie Di Guilmi, André Zapun, Claire Durmort
A method for labeling teichoic acids in the human pathogen Streptococcus pneumoniae has been developed using a "one-pot" two steps metabolic labeling approach. The essential nutriment choline modified with an azido-group was incorporated and exposed at the cell surface more rapidly than it reacted with the strain promoted azide alkyne cycloaddition SPAAC partner also present in the medium. Once at the cell surface on teichoic acids, coupling of the azido-group could then occur within 5 min by the bio-orthogonal click reaction with a DIBO-linked fluorophore...
July 16, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30005156/hydrogen-bond-surrogate-stabilization-of-%C3%AE-hairpins
#5
Nicholas Sawyer, Paramjit S Arora
Peptide secondary and tertiary structure motifs frequently serve as inspiration for the development of protein-protein interaction (PPI) inhibitors. While a wide variety of strategies have been used to stabilize or imitate α-helices, similar strategies for β-sheet stabilization are more limited. Synthetic scaffolds that stabilize reverse turns, individual β-strands, and cross-strand interactions have provided important insights into β-sheet stability and folding. However, these templates occupy regions of the β-sheet that might impact the β-sheet's ability to bind at a PPI interface...
July 13, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30004670/chemoproteomics-enabled-covalent-ligand-screening-reveals-aldh3a1-as-a-lung-cancer-therapy-target
#6
Jessica L Counihan, Amanda L Wiggenhorn, Kimberly E Anderson, Daniel K Nomura
Chemical genetics is a powerful approach for identifying therapeutically active small-molecules, but identifying the mechanisms of action underlying hit compounds remains challenging. Chemoproteomic platforms have arisen to tackle this challenge and enable rapid mechanistic deconvolution of small-molecule screening hits. Here, we have screened a cysteine-reactive covalent ligand library to identify hit compounds that impair cell survival and proliferation in non-small cell lung carcinoma cells, but not in primary human bronchial epithelial cells...
July 13, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29989390/engineered-flumazenil-recognition-site-provides-mechanistic-insight-governing-benzodiazepine-modulation-in-gaba-a-receptors
#7
David C B Siebert, Konstantina Bampali, Roshan Puthenkalam, Zdravko Varagic, Isabella Sarto-Jackson, Petra Scholze, Werner Sieghart, Marko D Mihovilovic, Michael Schnürch, Margot Ernst
The anxiolytic, anticonvulsant, muscle-relaxant and sedative-hypnotic effects of benzodiazepine site ligands are mainly elicited by allosteric modulation of GABAA receptors via their extracellular αx+/γ2- (x = 1,2,3,5) interfaces. In addition, a low affinity binding site at the homologous α+/β- interfaces was reported for some benzodiazepine site ligands. Classical benzodiazepines and pyrazoloquinolinones have been used as molecular probes to develop structure activity relationship models for benzodiazepine site activity...
July 10, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29979576/targeted-elimination-of-tumorigenic-human-pluripotent-stem-cells-using-suicide-inducing-virus-like-particles
#8
Antonio Rampoldi, Stephen N Crooke, Marcela K Preininger, Rajneesh Jha, Joshua Maxwell, Lingmei Ding, Paul Spearman, M G Finn, Chunhui Xu
Sensitization to prodrugs via transgenic expression of suicide genes is a leading strategy for the selective elimination of potentially tumorigenic human pluripotent stem cells (hPSCs) in regenerative medicine, but transgenic modification poses safety risks such as deleterious mutagenesis. We describe here an alternative method of delivering suicide-inducing molecules explicitly to hPSCs using virus-like particles (VLPs), and demonstrate its use in eliminating undifferentiated hPSCs in vitro. VLPs were engineered from Qβ bacteriophage capsids to contain enhanced green fluorescent protein (EGFP) or cytosine deaminase (CD), and to simultaneously display multiple IgG-binding ZZ domains...
July 6, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29979567/directed-accumulation-of-anticancer-depsipeptides-by-characterization-of-neoantimycins-biosynthetic-pathway-and-an-nadph-dependent-reductase
#9
Yongjun Zhou, Xiao Lin, Simon R Williams, Liyun Liu, Yaoyao Shen, Shu-Ping Wang, Fan Sun, Shihai Xu, Hai Deng, Peter F Leadlay, Hou-Wen Lin
Neoantimycins (NATs) are members of antimycin-type of depsipeptides with outstanding anticancer activities. We isolated NAT-A (1) and -F (2) from the fermentation extract of Streptomyces conglobatus. The NAT biosynthetic gene cluster (nat BGC) was identified by genome sequencing and bioinformatics analysis. nat BGC includes two nonribosomal peptide synthetases (NRPSs) and one polyketide synthase (PKS) genes, and a gene cassette (ten genes), of which the encoded enzymes share high homologs to the ones responsible for 3-formamidosalicylate (3-FAS) biosynthesis in antimycin biosynthetic pathway...
July 6, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29966080/cytochrome-c-reduction-by-h-2-s-potentiates-sulfide-signaling
#10
Victor Vitvitsky, Jan Lj Miljkovic, Trever Bostelaar, Bikash Adhikari, Pramod K Yadav, Andrea K Steiger, Roberta Torregrossa, Michael D Pluth, Matthew Whiteman, Ruma Banerjee, Milos R Filipovic
Hydrogen sulfide (H2 S) is an endogenously produced gas that is toxic at high concentrations. It is disposed of by a dedicated mitochondrial sulfide oxidation pathway, which connects to the electron transfer chain at the level of complex III. Direct reduction of cytochrome C (Cyt C) by H2 S has been reported previously but not characterized. In this study, we demonstrate that reduction of ferric cytochrome C (Cyt C) by H2 S exhibits hysteretic behavior, which suggests the involvement of reactive sulfur species in the reduction process and is consistent with a reaction stoichiometry of 1...
July 2, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29966079/global-protein-stabilization-does-not-suffice-to-prevent-amyloid-fibril-formation
#11
Patrizia Marinelli, Susanna Navarro, Manuel Bano Polo, Bertrand Morel, Ricardo Graña-Montes, Anna Sabé, Francesc Canals, Maria Rosario Fernandez, Francisco Conejero-Lara, Salvador Ventura
Mutations or cellular conditions that destabilize the native protein conformation promote the population of partially unfolded conformations, that, in many cases, assemble into insoluble amyloid fibrils, a process associated with multiple human pathologies. Therefore, stabilization of protein structures is seen as an efficient way to prevent misfolding and subsequent aggregation. This has been suggested to be the underlying reason why proteins living in harsh environments, such as the extracellular space, have evolved disulfide bonds...
July 2, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29966078/a-potent-conformation-constrained-synthetic-peptide-mimic-of-a-homeodomain-selectively-regulates-target-genes-in-cells
#12
Basusree Ghosh, Liberalis Debraj Boila, Susobhan Choudhury, Priya Mondal, Sayan Bhattacharjee, Samir Kumar Pal, Amitava Sengupta, Siddhartha Roy
DNA as a target for therapeutic intervention, remains largely unexplored. DLX-4, a homeodomain-containing transcription factor, and its spliced isoforms play crucial roles in many aspects of cellular biochemistry and important roles in many diseases. A smaller peptide mimicking the homeodomain of the transcription factor DLX-4 was designed and synthesized by suitable conjoining of its modified DNA-binding elements. The peptide binds to DLX-4 target sites on the regulatory region of the globin gene cluster with native-like affinity and specificity in vitro...
July 2, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29965728/solid-state-nmr-studies-of-intact-lipopolysaccharide-endotoxin
#13
Cedric Laguri, Alba Silipo, Alessandra M Martorana, Paul Schanda, Roberta Marchetti, Alessandra Polissi, Antonio Molinaro, Jean-Pierre Simorre
Lipopolysaccharides (LPS) are complex glycolipids forming the outside layer of Gram-negative bacteria. Their hydrophobic and heterogeneous nature greatly hampers their structural study in an environment similar to the bacterial surface. We have studied LPS purified from E. coli and pathogenic P. aeruginosa with long O-antigen polysaccharides assembled in solution as vesicles or elongated micelles. Solid-state NMR with magic-angle spinning permitted the identification of NMR signals arising from regions with different flexibilities in the LPS, from the lipid components to the O-antigen polysaccharides...
July 2, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29963852/a-spontaneously-blinking-fluorescent-protein-for-simple-single-laser-super-resolution-live-cell-imaging
#14
Yoshiyuki Arai, Hiroki Takauchi, Yuhei Ogami, Satsuki Fujiwara, Masahiro Nakano, Tomoki Matsuda, Takeharu Nagai
Super-resolution imaging techniques based on single molecule localization microscopy (SMLM) broke the diffraction limit of optical microscopy in living samples with the aid of photoswitchable fluorescent probes and intricate microscopy systems. Here, we developed a fluorescent protein, SPOON, which can be switched-off by excitation light illumination and switched-on by thermally-induced dehydration resulting in an apparent spontaneous blinking behavior. This unique property of SPOON provides a simple SMLM-based super-resolution imaging platform which requires only a single 488 nm laser...
July 2, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29963848/lipidomics-suggests-a-new-role-for-ceramide-synthase-in-phagocytosis
#15
Divya Pathak, Neelay Mehendale, Shubham Singh, Roop Mallik, Siddhesh S Kamat
Phagocytosis is an evolutionarily conserved biological process where pathogens or cellular debris are cleared by engulfing them in a membrane-enclosed cellular compartment called the phagosome. The formation, maturation and subsequent degradation of a phagosome is an important immune response essential for protection against many pathogens. Yet, the global lipid profile of phagosomes remains unknown, especially as a function of their maturation in immune cells. Here we show using mass spectrometry based quantitative lipidomics that the ceramide class of lipids, especially very long chain ceramides, are enriched on maturing phagosomes with a concomitant decrease in the biosynthetic precursors of ceramides...
July 2, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29952541/antifungal-activity-of-%C3%AE-sarcin-against-penicillium-digitatum-proposal-of-a-new-role-for-fungal-ribotoxins
#16
Lucía Citores, Rosario Iglesias, Sara Ragucci, Antimo Di Maro, José M Ferreras
Among the putative defense proteins that occur in fungi, one of the best studied is α-sarcin, produced by the mold Aspergillus giganteus. This protein is the most significant member of the ribotoxin family, which consists of extracellular rRNA ribonucleases that display cytotoxic activity toward animal cells. Ribotoxins are rRNA endonucleases that catalyze the hydrolysis of the phosphodiester bond between G4325 and A4326 from the rat 28S rRNA. The results of several experimental approaches have led to propose ribotoxins as insecticidal agents...
June 29, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29953201/multistep-inhibition-of-%C3%AE-synuclein-aggregation-and-toxicity-in-vitro-and-in-vivo-by-trodusquemine
#17
Michele Perni, Patrick Flagmeier, Ryan Limbocker, Roberta Cascella, Francesco A Aprile, Céline Galvagnion, Gabriella T Heller, Georg Meisl, Serene W Chen, Janet R Kumita, Pavan K Challa, Julius B Kirkegaard, Samuel I A Cohen, Benedetta Mannini, Denise Barbut, Ellen A A Nollen, Cristina Cecchi, Nunilo Cremades, Tuomas P J Knowles, Fabrizio Chiti, Michael Zasloff, Michele Vendruscolo, Christopher M Dobson
The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the related compound trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan...
June 28, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29952553/parathyroid-hormone-senses-extracellular-calcium-to-modulate-endocrine-signaling-upon-binding-to-the-family-b-gpcr-parathyroid-hormone-1-receptor
#18
Kelly J Culhane, Morgan E Belina, Jeremiah N Sims, Yingying Cai, Yuting Liu, Pam S P Wang, Elsa C Y Yan
Parathyroid hormone (PTH) binds to a family B G protein coupled receptor, parathyroid hormone 1 receptor (PTH1R). One of its functions is to regulate Ca2+ homeostasis in bone remodeling, during which Ca2+ can reach up to 40 mM. A truncated version of PTH, PTH(1-34), can fully activate PTH1R and has been used for osteoporosis treatments. Here, we used fluorescence anisotropy to examine the binding of PTH(1-34) to PTH1R purified in nanodiscs (PTH1R-ND) and found that the affinity increases 5-fold in the presence of 15 mM Ca2+ ...
June 28, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29905467/lov-domains-in-the-design-of-photoresponsive-enzymes
#19
Swantje Seifert, Susanne Brakmann
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 occurring 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...
June 28, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29897731/small-molecule-inhibitors-of-nfkb-reverse-iron-overload-and-hepcidin-deregulation-in-a-zebrafish-model-for-hereditary-hemochromatosis-type-3
#20
Sandeep Basu, Kanika Jalodia, Shashi Ranjan, Jing-Ruey J Yeh, Randall T Peterson, Chetana Sachidanandan
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. The tfr2 mutant model in zebrafish recapitulates the defining features of HH3: iron overload and suppression of hepcidin, the iron regulatory hormone...
June 28, 2018: ACS Chemical Biology
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