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Nature Chemical Biology

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https://www.readbyqxmd.com/read/28437396/immunology-mind-the-immuno-connection-gap
#1
Wolfgang Link
No abstract text is available yet for this article.
April 24, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28437395/global-survey-of-the-immunomodulatory-potential-of-common-drugs
#2
Gregory I Vladimer, Berend Snijder, Nikolaus Krall, Johannes W Bigenzahn, Kilian V M Huber, Charles-Hugues Lardeau, Kumar Sanjiv, Anna Ringler, Ulrika Warpman Berglund, Monika Sabler, Oscar Lopez de la Fuente, Paul Knöbl, Stefan Kubicek, Thomas Helleday, Ulrich Jäger, Giulio Superti-Furga
Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, ∼10% of the agents tested affected these cell-cell interactions differentially...
April 24, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28437394/selective-degradation-of-splicing-factor-caper%C3%AE-by-anticancer-sulfonamides
#3
Taisuke Uehara, Yukinori Minoshima, Koji Sagane, Naoko Hata Sugi, Kaoru Ogawa Mitsuhashi, Noboru Yamamoto, Hiroshi Kamiyama, Kentaro Takahashi, Yoshihiko Kotake, Mai Uesugi, Akira Yokoi, Atsushi Inoue, Taku Yoshida, Miyuki Mabuchi, Akito Tanaka, Takashi Owa
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4(DCAF15) mediated ubiquitination in human cancer cell lines...
April 24, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28437393/protein-degradation-dcafinating-splicing
#4
Georg E Winter
No abstract text is available yet for this article.
April 24, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28414711/the-pimeloyl-coa-synthetase-biow-defines-a-new-fold-for-adenylate-forming-enzymes
#5
Paola Estrada, Miglena Manandhar, Shi-Hui Dong, Jaigeeth Deveryshetty, Vinayak Agarwal, John E Cronan, Satish K Nair
Reactions that activate carboxylates through acyl-adenylate intermediates are found throughout biology and include acyl- and aryl-CoA synthetases and tRNA synthetases. Here we describe the characterization of Aquifex aeolicus BioW, which represents a new protein fold within the superfamily of adenylating enzymes. Substrate-bound structures identified the enzyme active site and elucidated the mechanistic strategy for conjugating CoA to the seven-carbon α,ω-dicarboxylate pimelate, a biotin precursor. Proper position of reactive groups for the two half-reactions is achieved solely through movements of active site residues, as confirmed by site-directed mutational analysis...
April 17, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28414710/using-the-pimeloyl-coa-synthetase-adenylation-fold-to-synthesize-fatty-acid-thioesters
#6
Menglu Wang, Lucile Moynié, Peter J Harrison, Van Kelly, Andrew Piper, James H Naismith, Dominic J Campopiano
Biotin is an essential vitamin in plants and mammals, functioning as the carbon dioxide carrier within central lipid metabolism. Bacterial pimeloyl-CoA synthetase (BioW) acts as a highly specific substrate-selection gate, ensuring the integrity of the carbon chain in biotin synthesis. BioW catalyzes the condensation of pimelic acid (C7 dicarboxylic acid) with CoASH in an ATP-dependent manner to form pimeloyl-CoA, the first dedicated biotin building block. Multiple structures of Bacillus subtilis BioW together capture all three substrates, as well as the intermediate pimeloyl-adenylate and product pyrophosphate (PPi), indicating that the enzyme uses an internal ruler to select the correct dicarboxylic acid substrate...
April 17, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28398287/crispr-cas9-strategy-for-activation-of-silent-streptomyces-biosynthetic-gene-clusters
#7
Mingzi M Zhang, Fong Tian Wong, Yajie Wang, Shangwen Luo, Yee Hwee Lim, Elena Heng, Wan Lin Yeo, Ryan E Cobb, Behnam Enghiad, Ee Lui Ang, Huimin Zhao
Here we report an efficient CRISPR-Cas9 knock-in strategy to activate silent biosynthetic gene clusters (BGCs) in streptomycetes. We applied this one-step strategy to activate multiple BGCs of different classes in five Streptomyces species and triggered the production of unique metabolites, including a novel pentangular type II polyketide in Streptomyces viridochromogenes. This potentially scalable strategy complements existing activation approaches and facilitates discovery efforts to uncover new compounds with interesting bioactivities...
April 10, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28394885/mechanistic-insights-into-energy-conservation-by-flavin-based-electron-bifurcation
#8
Carolyn E Lubner, David P Jennings, David W Mulder, Gerrit J Schut, Oleg A Zadvornyy, John P Hoben, Monika Tokmina-Lukaszewska, Luke Berry, Diep M Nguyen, Gina L Lipscomb, Brian Bothner, Anne K Jones, Anne-Frances Miller, Paul W King, Michael W W Adams, John W Peters
The recently realized biochemical phenomenon of energy conservation through electron bifurcation provides biology with an elegant means to maximize utilization of metabolic energy. The mechanism of coordinated coupling of exergonic and endergonic oxidation-reduction reactions by a single enzyme complex has been elucidated through optical and paramagnetic spectroscopic studies revealing unprecedented features. Pairs of electrons are bifurcated over more than 1 volt of electrochemical potential by generating a low-potential, highly energetic, unstable flavin semiquinone and directing electron flow to an iron-sulfur cluster with a highly negative potential to overcome the barrier of the endergonic half reaction...
April 10, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28369041/atat-blocks-translation-initiation-by-n-acetylation-of-the-initiator-trna-fmet
#9
Dukas Jurėnas, Sneha Chatterjee, Albert Konijnenberg, Frank Sobott, Louis Droogmans, Abel Garcia-Pino, Laurence Van Melderen
Toxin-antitoxin (TA) loci are prevalent in bacterial genomes. They are suggested to play a central role in dormancy and persister states. Under normal growth conditions, TA toxins are neutralized by their cognate antitoxins, and under stress conditions, toxins are freed and inhibit essential cellular processes using a variety of mechanisms. Here we characterize ataR-ataT, a novel TA system, from enterohemorrhagic Escherichia coli. We show that the toxin AtaT is a GNAT family enzyme that transfers an acetyl group from acetyl coenzyme A to the amine group of the methionyl aminoacyl moiety of initiator tRNA...
April 3, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28369040/phosphorylated-glycosphingolipids-essential-for-cholesterol-mobilization-in-caenorhabditis-elegans
#10
Sebastian Boland, Ulrike Schmidt, Vyacheslav Zagoriy, Julio L Sampaio, Raphael F Fritsche, Regina Czerwonka, Tilo Lübken, Jakob Reimann, Sider Penkov, Hans-Joachim Knölker, Teymuras V Kurzchalia
The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is indispensable. Here, we present a novel class of C. elegans phosphorylated glycosphingolipids, phosphoethanolamine glucosylceramides (PEGCs), capable of rescuing larval arrest induced by sterol starvation. We describe the total synthesis of a major PEGC species and demonstrate that the PEGC synthetic counterpart suppresses the dauer-constitutive phenotype of Niemann-Pick C1 (NPC1) and DAF-7/TGF-β mutant worms caused by impaired intracellular sterol trafficking...
April 3, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346407/insights-into-activity-and-inhibition-from-the-crystal-structure-of-human-o-glcnacase
#11
Nathaniel L Elsen, Sangita B Patel, Rachael E Ford, Dawn L Hall, Fred Hess, Hari Kandula, Maria Kornienko, John Reid, Harold Selnick, Jennifer M Shipman, Sujata Sharma, Kevin J Lumb, Stephen M Soisson, Daniel J Klein
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346406/diabetes-reversal-by-inhibition-of-the-low-molecular-weight-tyrosine-phosphatase
#12
Stephanie M Stanford, Alexander E Aleshin, Vida Zhang, Robert J Ardecky, Michael P Hedrick, Jiwen Zou, Santhi R Ganji, Matthew R Bliss, Fusayo Yamamoto, Andrey A Bobkov, Janna Kiselar, Yingge Liu, Gregory W Cadwell, Shilpi Khare, Jinghua Yu, Antonio Barquilla, Thomas D Y Chung, Tomas Mustelin, Simon Schenk, Laurie A Bankston, Robert C Liddington, Anthony B Pinkerton, Nunzio Bottini
Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346405/structural-and-functional-insight-into-human-o-glcnacase
#13
Christian Roth, Sherry Chan, Wendy A Offen, Glyn R Hemsworth, Lianne I Willems, Dustin T King, Vimal Varghese, Robert Britton, David J Vocadlo, Gideon J Davies
O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346404/chemical-screening-identifies-atm-as-a-target-for-alleviating-senescence
#14
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Yongsub Kim, Hyo Jei Claudia Choi, Chul Won Jung, Young-Sam Lee, Sang Chul Park
Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346403/near-infrared-optogenetic-pair-for-protein-regulation-and-spectral-multiplexing
#15
Taras A Redchuk, Evgeniya S Omelina, Konstantin G Chernov, Vladislav V Verkhusha
Multifunctional optogenetic systems are in high demand for use in basic and biomedical research. Near-infrared-light-inducible binding of bacterial phytochrome BphP1 to its natural PpsR2 partner is beneficial for simultaneous use with blue-light-activatable tools. However, applications of the BphP1-PpsR2 pair are limited by the large size, multidomain structure and oligomeric behavior of PpsR2. Here, we engineered a single-domain BphP1 binding partner, Q-PAS1, which is three-fold smaller and lacks oligomerization...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28319101/a-vibrio-cholerae-autoinducer-receptor-pair-that-controls-biofilm-formation
#16
Kai Papenfort, Justin E Silpe, Kelsey R Schramma, Jian-Ping Cong, Mohammad R Seyedsayamdost, Bonnie L Bassler
Quorum sensing (QS) is a cell-cell communication process that enables bacteria to track cell population density and orchestrate collective behaviors. QS relies on the production and detection of, and the response to, extracellular signal molecules called autoinducers. In Vibrio cholerae, multiple QS circuits control pathogenesis and biofilm formation. Here, we identify and characterize a new QS autoinducer-receptor pair. The autoinducer is 3,5-dimethylpyrazin-2-ol (DPO). DPO is made from threonine and alanine, and its synthesis depends on threonine dehydrogenase (Tdh)...
May 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28319100/metagenomic-discovery-of-polybrominated-diphenyl-ether-biosynthesis-by-marine-sponges
#17
Vinayak Agarwal, Jessica M Blanton, Sheila Podell, Arnaud Taton, Michelle A Schorn, Julia Busch, Zhenjian Lin, Eric W Schmidt, Paul R Jensen, Valerie J Paul, Jason S Biggs, James W Golden, Eric E Allen, Bradley S Moore
Naturally produced polybrominated diphenyl ethers (PBDEs) pervade the marine environment and structurally resemble toxic man-made brominated flame retardants. PBDEs bioaccumulate in marine animals and are likely transferred to the human food chain. However, the biogenic basis for PBDE production in one of their most prolific sources, marine sponges of the order Dysideidae, remains unidentified. Here, we report the discovery of PBDE biosynthetic gene clusters within sponge-microbiome-associated cyanobacterial endosymbionts through the use of an unbiased metagenome-mining approach...
May 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28319099/the-direct-role-of-selenocysteine-in-nifese-hydrogenase-maturation-and-catalysis
#18
Marta C Marques, Cristina Tapia, Oscar Gutiérrez-Sanz, Ana Raquel Ramos, Kimberly L Keller, Judy D Wall, Antonio L De Lacey, Pedro M Matias, Inês A C Pereira
Hydrogenases are highly active enzymes for hydrogen production and oxidation. [NiFeSe] hydrogenases, in which selenocysteine is a ligand to the active site Ni, have high catalytic activity and a bias for H2 production. In contrast to [NiFe] hydrogenases, they display reduced H2 inhibition and are rapidly reactivated after contact with oxygen. Here we report an expression system for production of recombinant [NiFeSe] hydrogenase from Desulfovibrio vulgaris Hildenborough and study of a selenocysteine-to-cysteine variant (Sec489Cys) in which, for the first time, a [NiFeSe] hydrogenase was converted to a [NiFe] type...
May 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28288109/in-silico-design-of-novel-probes-for-the-atypical-opioid-receptor-mrgprx2
#19
Katherine Lansu, Joel Karpiak, Jing Liu, Xi-Ping Huang, John D McCorvy, Wesley K Kroeze, Tao Che, Hiroshi Nagase, Frank I Carroll, Jian Jin, Brian K Shoichet, Bryan L Roth
The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small-molecule MRGPRX2 agonists, selective nanomolar-potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found that many opioid compounds activated MRGPRX2, including (-)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan, and the prodynorphin-derived peptides dynorphin A, dynorphin B, and α- and β-neoendorphin...
May 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28288108/structural-basis-of-protac-cooperative-recognition-for-selective-protein-degradation
#20
Morgan S Gadd, Andrea Testa, Xavier Lucas, Kwok-Ho Chan, Wenzhang Chen, Douglas J Lamont, Michael Zengerle, Alessio Ciulli
Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4(BD2))...
May 2017: Nature Chemical Biology
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