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Nature Chemical Biology

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https://www.readbyqxmd.com/read/29334382/a-de-novo-enzyme-catalyzes-a-life-sustaining-reaction-in-escherichia-coli
#1
Ann E Donnelly, Grant S Murphy, Katherine M Digianantonio, Michael H Hecht
Producing novel enzymes that are catalytically active in vitro and biologically functional in vivo is a key goal of synthetic biology. Here we describe Syn-F4, the first de novo protein that meets both criteria. Purified Syn-F4 hydrolyzes the siderophore ferric enterobactin, and expression of Syn-F4 allows an inviable strain of Escherichia coli to grow in iron-limited medium. These findings demonstrate that entirely new sequences can provide life-sustaining enzymatic functions in living organisms.
January 15, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29334381/the-molecular-basis-of-subtype-selectivity-of-human-kinin-g-protein-coupled-receptors
#2
Lisa Joedicke, Jiafei Mao, Georg Kuenze, Christoph Reinhart, Tejaswi Kalavacherla, Hendrik R A Jonker, Christian Richter, Harald Schwalbe, Jens Meiler, Julia Preu, Hartmut Michel, Clemens Glaubitz
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors...
January 15, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29334380/light-activated-chemical-probing-of-nucleobase-solvent-accessibility-inside-cells
#3
Chao Feng, Dalen Chan, Jojo Joseph, Mikko Muuronen, William H Coldren, Nan Dai, Ivan R Corrêa, Filipp Furche, Christopher M Hadad, Robert C Spitale
The discovery of functional RNAs that are critical for normal and disease physiology continues to expand at a breakneck pace. Many RNA functions are controlled by the formation of specific structures, and an understanding of each structural component is necessary to elucidate its function. Measuring solvent accessibility intracellularly with experimental ease is an unmet need in the field. Here, we present a novel method for probing nucleobase solvent accessibility, Light Activated Structural Examination of RNA (LASER)...
January 15, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29309055/na-mimicking-ligands-stabilize-the-inactive-state-of-leukotriene-b4-receptor-blt1
#4
Tetsuya Hori, Toshiaki Okuno, Kunio Hirata, Keitaro Yamashita, Yoshiaki Kawano, Masaki Yamamoto, Masakatsu Hato, Motonao Nakamura, Takao Shimizu, Takehiko Yokomizo, Masashi Miyano, Shigeyuki Yokoyama
Most G-protein-coupled receptors (GPCRs) are stabilized in common in the inactive state by the formation of the sodium ion-centered water cluster with the conserved Asp2.50 inside the seven-transmembrane domain. We determined the crystal structure of the leukotriene B4 (LTB4) receptor BLT1 bound with BIIL260, a chemical bearing a benzamidine moiety. Surprisingly, the amidine group occupies the sodium ion and water locations, interacts with D662.50, and mimics the entire sodium ion-centered water cluster. Thus, BLT1 is fixed in the inactive state, and the transmembrane helices cannot change their conformations to form the active state...
January 8, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29309054/mechanism-of-intersubunit-ketosynthase-dehydratase-interaction-in-polyketide-synthases
#5
Matthew Jenner, Simone Kosol, Daniel Griffiths, Panward Prasongpholchai, Lucio Manzi, Andrew S Barrow, John E Moses, Neil J Oldham, Józef R Lewandowski, Gregory L Challis
Modular polyketide synthases (PKSs) produce numerous structurally complex natural products that have diverse applications in medicine and agriculture. PKSs typically consist of several multienzyme subunits that utilize structurally defined docking domains (DDs) at their N and C termini to ensure correct assembly into functional multiprotein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-acyltransferase (trans-AT) modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains...
January 8, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29309053/employing-a-biochemical-protecting-group-for-a-sustainable-indigo-dyeing-strategy
#6
Tammy M Hsu, Ditte H Welner, Zachary N Russ, Bernardo Cervantes, Ramya L Prathuri, Paul D Adams, John E Dueber
Indigo is an ancient dye uniquely capable of producing the signature tones in blue denim; however, the dyeing process requires chemical steps that are environmentally damaging. We describe a sustainable dyeing strategy that not only circumvents the use of toxic reagents for indigo chemical synthesis but also removes the need for a reducing agent for dye solubilization. This strategy utilizes a glucose moiety as a biochemical protecting group to stabilize the reactive indigo precursor indoxyl to form indican, preventing spontaneous oxidation to crystalline indigo during microbial fermentation...
January 8, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29291350/accessing-chemical-diversity-from-the-uncultivated-symbionts-of-small-marine-animals
#7
Thomas E Smith, Christopher D Pond, Elizabeth Pierce, Zachary P Harmer, Jason Kwan, Malcolm M Zachariah, Mary Kay Harper, Thomas P Wyche, Teatulohi K Matainaho, Tim S Bugni, Louis R Barrows, Chris M Ireland, Eric W Schmidt
Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea. Tunicates are a reservoir for new bioactive chemicals, yet their small size often impedes identification or even detection of the chemicals within...
January 1, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29291349/an-opr3-independent-pathway-uses-4-5-didehydrojasmonate-for-jasmonate-synthesis
#8
Andrea Chini, Isabel Monte, Angel M Zamarreño, Mats Hamberg, Steve Lassueur, Philippe Reymond, Sally Weiss, Annick Stintzi, Andreas Schaller, Andrea Porzel, José M García-Mina, Roberto Solano
Biosynthesis of the phytohormone jasmonoyl-isoleucine (JA-Ile) requires reduction of the JA precursor 12-oxo-phytodienoic acid (OPDA) by OPDA reductase 3 (OPR3). Previous analyses of the opr3-1 Arabidopsis mutant suggested an OPDA signaling role independent of JA-Ile and its receptor COI1; however, this hypothesis has been challenged because opr3-1 is a conditional allele not completely impaired in JA-Ile biosynthesis. To clarify the role of OPR3 and OPDA in JA-independent defenses, we isolated and characterized a loss-of-function opr3-3 allele...
January 1, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29251720/pharmacological-perturbation-of-cdk9-using-selective-cdk9-inhibition-or-degradation
#9
Calla M Olson, Baishan Jiang, Michael A Erb, Yanke Liang, Zainab M Doctor, Zinan Zhang, Tinghu Zhang, Nicholas Kwiatkowski, Myriam Boukhali, Jennifer L Green, Wilhelm Haas, Tyzoon Nomanbhoy, Eric S Fischer, Richard A Young, James E Bradner, Georg E Winter, Nathanael S Gray
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets...
December 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29251719/expression-system-for-structural-and-functional-studies-of-human-glycosylation-enzymes
#10
Kelley W Moremen, Annapoorani Ramiah, Melissa Stuart, Jason Steel, Lu Meng, Farhad Forouhar, Heather A Moniz, Gagandeep Gahlay, Zhongwei Gao, Digantkumar Chapla, Shuo Wang, Jeong-Yeh Yang, Pradeep Kumar Prabhakar, Roy Johnson, Mitche Dela Rosa, Christoph Geisler, Alison V Nairn, Jayaraman Seetharaman, Sheng-Cheng Wu, Liang Tong, Harry J Gilbert, Joshua LaBaer, Donald L Jarvis
Vertebrate glycoproteins and glycolipids are synthesized in complex biosynthetic pathways localized predominantly within membrane compartments of the secretory pathway. The enzymes that catalyze these reactions are exquisitely specific, yet few have been extensively characterized because of challenges associated with their recombinant expression as functional products. We used a modular approach to create an expression vector library encoding all known human glycosyltransferases, glycoside hydrolases, and sulfotransferases, as well as other glycan-modifying enzymes...
December 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29251718/a-role-for-2-cys-peroxiredoxins-in-facilitating-cytosolic-protein-thiol-oxidation
#11
Sarah Stöcker, Michael Maurer, Thomas Ruppert, Tobias P Dick
Hydrogen peroxide (H2O2) acts as a signaling messenger by triggering the reversible oxidation of redox-regulated proteins. It remains unclear how proteins can be oxidized by signaling levels of H2O2 in the presence of peroxiredoxins, which are highly efficient peroxide scavengers. Here we show that the rapid formation of disulfide bonds in cytosolic proteins is enabled, rather than competed, by cytosolic 2-Cys peroxiredoxins. Under the conditions tested, the combined deletion or depletion of cytosolic peroxiredoxins broadly frustrated H2O2-dependent protein thiol oxidation, which is the exact opposite of what would be predicted based on the assumption that H2O2 oxidizes proteins directly...
December 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29227473/structure-inspired-design-of-%C3%AE-arrestin-biased-ligands-for-aminergic-gpcrs
#12
John D McCorvy, Kyle V Butler, Brendan Kelly, Katie Rechsteiner, Joel Karpiak, Robin M Betz, Bethany L Kormos, Brian K Shoichet, Ron O Dror, Jian Jin, Bryan L Roth
Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands...
December 11, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29227472/engineered-synthetic-scaffolds-for-organizing-proteins-within-the-bacterial-cytoplasm
#13
Matthew J Lee, Judith Mantell, Lorna Hodgson, Dominic Alibhai, Jordan M Fletcher, Ian R Brown, Stefanie Frank, Wei-Feng Xue, Paul Verkade, Derek N Woolfson, Martin J Warren
We have developed a system for producing a supramolecular scaffold that permeates the entire Escherichia coli cytoplasm. This cytoscaffold is constructed from a three-component system comprising a bacterial microcompartment shell protein and two complementary de novo coiled-coil peptides. We show that other proteins can be targeted to this intracellular filamentous arrangement. Specifically, the enzymes pyruvate decarboxylase and alcohol dehydrogenase have been directed to the filaments, leading to enhanced ethanol production in these engineered bacterial cells compared to those that do not produce the scaffold...
December 11, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29227471/inhibiting-mitochondrial-phosphate-transport-as-an-unexploited-antifungal-strategy
#14
Catherine A McLellan, Benjamin M Vincent, Norma V Solis, Alex K Lancaster, Lucas B Sullivan, Cathy L Hartland, Willmen Youngsaye, Scott G Filler, Luke Whitesell, Susan Lindquist
The development of effective antifungal therapeutics remains a formidable challenge because of the close evolutionary relationship between humans and fungi. Mitochondrial function may present an exploitable vulnerability because of its differential utilization in fungi and its pivotal roles in fungal morphogenesis, virulence, and drug resistance already demonstrated by others. We now report mechanistic characterization of ML316, a thiohydantoin that kills drug-resistant Candida species at nanomolar concentrations through fungal-selective inhibition of the mitochondrial phosphate carrier Mir1...
December 11, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29200207/human-antibody-based-chemically-induced-dimerizers-for-cell-therapeutic-applications
#15
Zachary B Hill, Alexander J Martinko, Duy P Nguyen, James A Wells
Chemically induced dimerizers (CIDs) have emerged as one of the most powerful tools for artificially regulating signaling pathways in cells; however, currently available CID systems lack the properties desired for use in regulating cellular therapies. Here, we report the development of human antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule-protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. We demonstrate this concept by generating three antibodies that are highly selective for the BCL-xL-ABT-737 complex compared to BCL-xL alone...
December 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29200206/discovery-and-characterization-of-highly-potent-and-selective-allosteric-usp7-inhibitors
#16
Gerald Gavory, Colin R O'Dowd, Matthew D Helm, Jakub Flasz, Elias Arkoudis, Anthony Dossang, Caroline Hughes, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Oliver Barker, Hugues Miel, Timothy Harrison
Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC50 < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts...
December 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29176672/5-formylcytosine-to-cytosine-conversion-by-c-c-bond-cleavage-in-vivo
#17
Katharina Iwan, René Rahimoff, Angie Kirchner, Fabio Spada, Arne S Schröder, Olesea Kosmatchev, Shqiponja Ferizaj, Jessica Steinbacher, Edris Parsa, Markus Müller, Thomas Carell
Tet enzymes oxidize 5-methyl-deoxycytidine (mdC) to 5-hydroxymethyl-dC (hmdC), 5-formyl-dC (fdC) and 5-carboxy-dC (cadC) in DNA. It was proposed that fdC and cadC deformylate and decarboxylate, respectively, to dC over the course of an active demethylation process. This would re-install canonical dC bases at previously methylated sites. However, whether such direct C-C bond cleavage reactions at fdC and cadC occur in vivo remains an unanswered question. Here we report the incorporation of synthetic isotope- and (R)-2'-fluorine-labeled dC and fdC derivatives into the genome of cultured mammalian cells...
November 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29176671/inhibition-of-delta-induced-notch-signaling-using-fucose-analogs
#18
Michael Schneider, Vivek Kumar, Lars Ulrik Nordstrøm, Lei Feng, Hideyuki Takeuchi, Huilin Hao, Vincent C Luca, K Christopher Garcia, Pamela Stanley, Peng Wu, Robert S Haltiwanger
Notch is a cell-surface receptor that controls cell-fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools that inhibit Notch activity are being developed as cancer therapeutics. To this end, we screened L-fucose analogs for their effects on Notch signaling...
November 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29155430/engineering-peptide-ligase-specificity-by-proteomic-identification-of-ligation-sites
#19
Amy M Weeks, James A Wells
Enzyme-catalyzed peptide ligation is a powerful tool for site-specific protein bioconjugation, but stringent enzyme-substrate specificity limits its utility. We developed an approach for comprehensively characterizing peptide ligase specificity for N termini using proteome-derived peptide libraries. We used this strategy to characterize the ligation efficiency for >25,000 enzyme-substrate pairs in the context of the engineered peptide ligase subtiligase and identified a family of 72 mutant subtiligases with activity toward N-terminal sequences that were previously recalcitrant to modification...
November 20, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29155429/monobactam-formation-in-sulfazecin-by-a-nonribosomal-peptide-synthetase-thioesterase
#20
Ryan A Oliver, Rongfeng Li, Craig A Townsend
The N-sulfonated monocyclic β-lactam ring characteristic of the monobactams confers resistance to zinc metallo-β-lactamases and affords the most effective class to combat carbapenem-resistant enterobacteria (CRE). Here we report unprecedented nonribosomal peptide synthetase activities, wherein an assembled tripeptide is N-sulfonated in trans before direct synthesis of the β-lactam ring in a noncanonical, cysteine-containing thioesterase domain. This means of azetidinone synthesis is distinct from the three others known in nature...
November 20, 2017: Nature Chemical Biology
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