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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28933823/two-color-810-nm-sted-nanoscopy-of-living-cells-with-endogenous-snap-tagged-fusion-proteins
#1
Alexey N Butkevich, Haisen Ta, Michael Ratz, Stefan Stold, Stefan Jakobs, Vladimir N Belov, Stefan W Hell
A 810 nm STED nanoscopy setup and an appropriate combination of two fluorescent dyes (Si-rhodamine 680SiR and carbopyronine 610CP) have been developed for near-IR live-cell superresolution imaging. Vimentin endogenously tagged using the CRISPR/Cas9 approach with the SNAP-tag, together with a non-covalent tubulin label, provided reliable and cell-to-cell reproducible dual-color confocal and STED imaging of the cytoskeleton in living cells.
September 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28933529/simultaneous-production-of-anabaenopetins-and-namalides-by-the-cyanobacterium-nostoc-sp-cena543
#2
Tania K Shishido, Jouni Jokela, David P Fewer, Matti Wahlsten, Marli F Fiore, Kaarina Sivonen
Anabaenopeptins are a diverse group of cyclic peptides, which contain an unusual ureido linkage. Namalides are shorter structural homologs of anabaenopeptins, which also contain an ureido linkage. The biosynthetic origins of namalides are unknown despite a strong resemblance to anabaenopeptins. Here we show the cyanobacterium Nostoc sp. CENA543 strain producing new (nostamide B-E (2, 4, 5 and 6)) and known variants of anabaenopeptins (schizopeptin 791 (1) and anabaenopeptin 807 (3)). Surprisingly, Nostoc sp...
September 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28925688/live-cell-imaging-of-mitochondrial-autophagy-with-a-novel-fluorescent-small-molecule
#3
Hidefumi Iwashita, Satoru Torii, Noriyoshi Nagahora, Munetaka Ishiyama, Kosei Shioji, Kazumi Sasamoto, Shigeomi Shimizu, Kentaro Okuma
There has been a growing interest in mitophagy, mitochondria-selective autophagy, which plays an essential role in maintaining intracellular homeostasis. We have developed a small-molecule fluorescent probe, Mtphagy Dye, for visualizing mitophagy, which was readily synthesized from a known perylene derivative, perylene-3,4-dicarboxylic anhydride. Mtphagy Dye has suitable fluorescent properties for detecting mitochondrial acidification during mitophagy at the long-wavelength region that does not damage mitochondria...
September 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28930429/mapping-protein-targets-of-bioactive-small-molecules-using-lipid-based-chemical-proteomics
#4
Kenneth M Lum, Yoshiaki Sato, Brittney A Beyer, Warren C Plaisted, Justin L Anglin, Luke L Lairson, Benjamin F Cravatt
Lipids play critical roles in cell biology, often through direct interactions with proteins. We recently described the use of photoreactive lipid probes combined with quantitative mass spectrometry to globally map lipid-protein interactions, and the effects of drugs on these interactions, in cells. Here, we investigate the broader potential of lipid-based chemical proteomic probes for determining the cellular targets of biologically active small molecules, including natural product derivatives and repurposed drugs of ill-defined mechanisms...
September 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28921948/baf180-its-roles-in-dna-repair-and-consequences-in-cancer
#5
Sarah Hopson, Martin J Thompson
In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating PBRM1 mutations to cancers has substantially increased. BAF180 has now been linked to more than 30 types of cancers, including ccRCC, cholangiocarcinomas, esophageal squamous cell carcinoma, bladder cancer, and breast cancer. The mutations associated with BAF180 are most often truncations, which result in loss of protein expression. This loss has been shown to adversely affect the expression of genes, likely because BAF180 is the chromatin recognition subunit of PBAF...
September 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28895730/rheostatic-control-of-cas9-mediated-dna-double-strand-break-dsb-generation-and-genome-editing
#6
John C Rose, Jason J Stephany, Cindy T Wei, Douglas M Fowler, Dustin J Maly
We recently reported two novel tools for precisely controlling and quantifying Cas9 activity: a chemically inducible Cas9 variant (ciCas9) that can be rapidly activated by small molecules and a ddPCR assay for time-resolved measurement of DNA double strand breaks (DSB-ddPCR). Here, we further demonstrate the potential of ciCas9 to function as a tunable rheostat for Cas9 function. We show that a new highly potent and selective small molecule activator paired with a more tightly regulated ciCas9 variant expands the range of accessible Cas9 activity levels...
September 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28829118/bioactive-natural-products-prioritization-using-massive-multi-informational-molecular-networks
#7
Florent Olivon, Pierre-Marie Allard, Alexey Koval, Davide Righi, Gregory Genta-Jouve, Johan Neyts, Cécile Apel, Christophe Pannecouque, Louis-Félix Nothias, Xavier Cachet, Laurence Marcourt, Fanny Roussi, Vladimir L Katanaev, David Touboul, Jean-Luc Wolfender, Marc Litaudon
Natural products represent an inexhaustible source of novel therapeutic agents. Their complex and constrained three-dimensional structures endow these molecules with exceptional biological properties, thereby giving them a major role in drug discovery programs. However, the search for new bioactive metabolites is hampered by the chemical complexity of the biological matrices in which they are found. The purification of single constituents from such matrices requires such a significant amount of work that it should be ideally performed only on molecules of high potential value (i...
September 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28910072/mapping-the-binding-site-for-escitalopram-and-paroxetine-in-the-human-serotonin-transporter-using-genetically-encoded-photocrosslinkers
#8
Hafsteinn Rannversson, Jacob Andersen, Benny Bang-Andersen, Kristian Strømgaard
In spite of the important role of the human serotonin transporter (hSERT) in depression treatment, the molecular details of how antidepressant drugs bind are still not completely understood, in particular those related to potential high- and low-affinity binding sites in hSERT. Here, we utilize amber codon suppression in hSERT to encode the photocrosslinking unnatural amino acid p-azido-L-phenylalanine into the suggested high- and low-affinity binding sites. We then employ UV-induced crosslinking with azF to map the binding site of escitalopram and paroxetine, two prototypical selective serotonin reuptake inhibitors (SSRIs)...
September 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28862425/btn3a1-discriminates-%C3%AE-%C3%AE-t-cell-phosphoantigens-from-nonantigenic-small-molecules-via-a-conformational-sensor-in-its-b30-2-domain
#9
Mahboob Salim, Timothy J Knowles, Alfie T Baker, Martin S Davey, Mark Jeeves, Pooja Sridhar, John Wilkie, Carrie R Willcox, Hachemi Kadri, Taher E Taher, Pierre Vantourout, Adrian Hayday, Youcef Mehellou, Fiyaz Mohammed, Benjamin E Willcox
Human Vγ9/Vδ2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells; however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag's are discriminated from nonantigenic small molecules. Here, we utilized NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1...
September 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28892616/chemoproteomics-enabled-covalent-ligand-screening-reveals-a-thioredoxin-caspase-3-interaction-disruptor-that-impairs-breast-cancer-pathogenicity
#10
Kimberly E Anderson, Milton To, James A Olzmann, Daniel K Nomura
Covalent ligand discovery is a promising strategy to develop small-molecule effectors against therapeutic targets. Recent studies have shown that dichlorotriazines are promising reactive scaffolds that preferentially react with lysines. Here, we have synthesized a series of dichlorotriazine-based covalent ligands and have screened this library to reveal small molecules that impair triple-negative breast cancer cell survival. Upon identifying a lead hit from this screen KEA1-97, we used activity-based protein profiling (ABPP)-based chemoproteomic platforms to identify that this compound targets lysine 72 of thioredoxin-a site previously shown to be important in protein interactions with caspase 3 to inhibit caspase 3 activity and suppress apoptosis...
September 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28892347/two-cooperative-glycosyltransferases-are-responsible-for-the-sugar-diversity-of-saquayamycins-isolated-from-streptomyces-sp-ky-40-1
#11
Shaimaa M Salem, Stevi Weidenbach, Jürgen Rohr
Glycosyltransferases are key enzymes involved in the biosynthesis of valuable natural products providing an excellent drug-tailoring tool. Herein, we report the identification of two cooperative glycosyltransferases from the sqn gene cluster directing the biosynthesis of saquayamycins in Streptomyces sp. KY40-1: SqnG1 and SqnG2. Gene inactivation of sqnG1 leads to 50-fold decrease in saquayamycin production, while inactivation of sqnG2 leads to complete production loss, suggesting that SqnG2 acts as dual O- and C-glycosyltransferase...
September 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28895717/backbone-circularization-coupled-with-optimization-of-connecting-segment-in-effectively-improving-the-stability-of-granulocyte-colony-stimulating-factor
#12
Takamitsu Miyafusa, Risa Shibuya, Wataru Nishima, Rie Ohara, Chuya Yoshida, Shinya Honda
Backbone circularization of protein is a powerful method to improve its structural stability. In this paper, we presumed that a tight connection leads to much higher stability. Therefore, we designed circularized variants of a granulocyte-colony stimulating factor (G-CSF) with a structurally optimized terminal connection. To estimate the appropriate length of the connection, we surveyed the Protein Data Bank to find local structures as a model for the connecting segment. We set the library of local structures composed of "helix-loop-helix," subsequently selected entries similar to the G-CSF terminus, and finally sorted the hit structures according to the loop length...
September 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28876896/differential-kinobeads-profiling-for-target-identification-of-irreversible-kinase-inhibitors
#13
Lars Dittus, Thilo Werner, Marcel Muelbaier, Marcus Bantscheff
Chemoproteomics profiling of kinase inhibitors with kinobeads enables the assessment of inhibitor potency and selectivity for endogenously expressed protein kinases in cell lines and tissues. Using a small panel of targeted covalent inhibitors, we demonstrate the importance of measuring covalent target binding in live cells. We present a differential kinobeads profiling strategy for covalent kinase inhibitors where a compound is added either to live cells or to a cell extract that enables the comprehensive assessment of inhibitor selectivity for covalent and noncovalent targets...
September 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28892625/platinum-binds-proteins-in-the-endoplasmic-reticulum-of-s-cerevisiae-and-induces-er-stress
#14
Rachael M Cunningham, Victoria J DeRose
Pt(II)-based anticancer drugs are widely used in the treatment of a variety of cancers, but their clinical efficacy is hindered by undesirable side effects and resistance. While much research has focused on Pt(II) drug interactions with DNA, there is increasing interest in proteins as alternative targets and contributors to cytotoxic and resistance mechanisms. Here we describe a chemical proteomic method for isolation and identification of cellular protein targets of platinum compounds using Pt(II) reagents that have been modified for participation in the 1,3 dipolar cycloaddition "click" reaction...
September 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28892606/crispr-mediated-tagging-of-endogenous-proteins-with-a-luminescent-peptide
#15
Marie K Schwinn, Thomas Machleidt, Kris Zimmerman, Christopher T Eggers, Andrew S Dixon, Robin Hurst, Mary P Hall, Lance P Encell, Brock F Binkowski, Keith V Wood
Intracellular signaling pathways are mediated by changes in protein abundance and post-translational modifications. A common approach for investigating intracellular signaling and the effects induced by synthetic compounds is to overexpress recombinant reporter genes within a cell. Genome editing with CRISPR/Cas9 offers a means to better preserve native biology by appending reporters directly onto the endogenous genes. An optimal reporter for this purpose would be small to negligibly influence intracellular processes, be readily linked to the endogenous genes with minimal experimental effort, and be sensitive enough to detect low expressing proteins...
September 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28892605/inhibitors-of-the-diadenosine-tetraphosphate-phosphorylase-rv2613c-of-mycobacterium-tuberculosis
#16
Kathrin H Götz, Stephan M Hacker, Daniel Mayer, Jan-Niklas Dürig, Steffen Stenger, Andreas Marx
The intracellular concentration of diadenosine tetraphospate (Ap4A) rises upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap4A are still enigmatic. If and how the varied Ap4A is a signal and involved in the signaling pathways leading to an appropriate cellular response, remains to be discovered. As the turnover of Ap4A by Ap4A cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of Ap4A...
September 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28886246/an-anion-%C3%AF-interaction-strongly-stabilizes-the-%C3%AE-sheet-protein-ww
#17
Mason S Smith, Eliza E K Lawrence, Wendy M Billings, Joshua L Price
Anions have long been known to engage in stabilizing interactions with electron-deficient arenes. However, the precise nature and energetic contribution of anion-π interactions to protein stability remains a subject of debate. Here we show that placing a negatively charged Asp in close proximity to electron-rich Phe in a reverse turn within the WW domain results in a favorable interaction that increases WW conformational stability by -1.3 kcal/mol.
September 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28846367/structure-and-functional-analysis-of-clbq-an-unusual-intermediate-releasing-thioesterase-from-the-colibactin-biosynthetic-pathway
#18
Naga Sandhya Guntaka, Alan R Healy, Jason M Crawford, Seth B Herzon, Steven D Bruner
Colibactin is a genotoxic hybrid nonribosomal peptide/polyketide secondary metabolite produced by various pathogenic and probiotic bacteria residing in the human gut. The presence of colibactin metabolites has been correlated to colorectal cancer formation in several studies. The specific function of many gene products in the colibactin gene cluster can be predicted. However, the role of ClbQ, a type II editing thioesterase, has not been established. The importance of ClbQ has been demonstrated by genetic deletions that abolish colibactin cytotoxic activity, and recent studies suggest an atypical role in releasing pathway intermediates from the assembly line...
September 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28880076/exploiting-overlapping-advantages-of-in-vitro-and-in-cellulo-selection-systems-to-isolate-a-novel-high-affinity-cjun-antagonist
#19
Daniel Baxter, Christopher G Ullman, Laura Frigotto, Jody M Mason
We have combined two peptide library-screening systems, exploiting the benefits offered by both to select novel antagonistic agents of cJun. CIS display is an in vitro cell-free system that allows very large libraries (≤10(14)) to be interrogated. However, affinity-based screening conditions can poorly reflect those relevant to therapeutic application, particularly for difficult intracellular targets, and can lead to false positives. In contrast, an in cellulo screening system such as the Protein-fragment Complementation Assay (PCA) selects peptides with high target affinity while additionally profiling for target specificity, protease resistance, solubility, and lack of toxicity in a more relevant context...
September 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28858479/functional-analysis-of-cytochrome-p450s-involved-in-streptovaricin-biosynthesis-and-generation-of-anti-mrsa-analogues
#20
Yuanzhen Liu, Xu Chen, Zhengyuan Li, Wei Xu, Weixin Tao, Jie Wu, Jian Yang, Zixin Deng, Yuhui Sun
The streptovaricins, chemically related to the rifamycins, are highly effective antibacterial agents, particularly against mycobacteria. Herein, a bioassay-guided investigation of Streptomyces spectabilis CCTCC M2017417 has led to the characterization of streptovaricins as potent compounds against methicillin-resistant Staphylococcus aureus (MRSA). We identified the streptovaricin biosynthetic gene cluster from S. spectabilis CCTCC M2017417 based on genomic sequencing and bioinformatic analysis. Targeted in-frame deletion of five cytochrome P450 genes (stvP1-P5) resulted in the identification of four new streptovaricin analogues and revealed the functions of these genes as follows: stvP1, stvP4, and stvP5 are responsible for the hydroxylation of C-20, Me-24, and C-28, respectively...
September 7, 2017: ACS Chemical Biology
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