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Nature Chemical Biology

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https://www.readbyqxmd.com/read/28092361/designed-cell-consortia-as-fragrance-programmable-analog-to-digital-converters
#1
Marius Müller, Simon Ausländer, Andrea Spinnler, David Ausländer, Julian Sikorski, Marc Folcher, Martin Fussenegger
Synthetic biology advances the rational engineering of mammalian cells to achieve cell-based therapy goals. Synthetic gene networks have nearly reached the complexity of digital electronic circuits and enable single cells to perform programmable arithmetic calculations or to provide dynamic remote control of transgenes through electromagnetic waves. We designed a synthetic multilayered gaseous-fragrance-programmable analog-to-digital converter (ADC) allowing for remote control of digital gene expression with 2-bit AND-, OR- and NOR-gate logic in synchronized cell consortia...
January 16, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092360/chemical-proteomics-reveals-adp-ribosylation-of-small-gtpases-during-oxidative-stress
#2
Nathan P Westcott, Joseph P Fernandez, Henrik Molina, Howard C Hang
ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N(6)-propargyl adenosine (N(6)pA), is metabolically incorporated in mammalian cells and enables fluorescence detection and proteomic analysis of ADP-ribosylated proteins. Notably, our analysis of N(6)pA-labeled proteins that are upregulated by oxidative stress revealed differential ADP-ribosylation of small GTPases...
January 16, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092359/lysine-relay-mechanism-coordinates-intermediate-transfer-in-vitamin-b6-biosynthesis
#3
Matthew J Rodrigues, Volker Windeisen, Yang Zhang, Gabriela Guédez, Stefan Weber, Marco Strohmeier, Jeremiah W Hanes, Antoine Royant, Gwyndaf Evans, Irmgard Sinning, Steven E Ealick, Tadhg P Begley, Ivo Tews
Substrate channeling has emerged as a common mechanism for enzymatic intermediate transfer. A conspicuous gap in knowledge concerns the use of covalent lysine imines in the transfer of carbonyl-group-containing intermediates, despite their wideuse in enzymatic catalysis. Here we show how imine chemistry operates in the transfer of covalent intermediates in pyridoxal 5'-phosphate biosynthesis by the Arabidopsis thaliana enzyme Pdx1. An initial ribose 5-phosphate lysine imine is converted to the chromophoric I320 intermediate, simultaneously bound to two lysine residues and partially vacating the active site, which creates space for glyceraldehyde 3-phosphate to bind...
January 16, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092358/recurrent-rna-motifs-as-scaffolds-for-genetically-encodable-small-molecule-biosensors
#4
Ely B Porter, Jacob T Polaski, Makenna M Morck, Robert T Batey
Allosteric RNA devices are increasingly being viewed as important tools capable of monitoring enzyme evolution, optimizing engineered metabolic pathways, facilitating gene discovery and regulators of nucleic acid-based therapeutics. A key bottleneck in the development of these platforms is the availability of small-molecule-binding RNA aptamers that robustly function in the cellular environment. Although aptamers can be raised against nearly any desired target through in vitro selection, many cannot easily be integrated into devices or do not reliably function in a cellular context...
January 16, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28068312/mray-antibiotic-complex-reveals-details-of-tunicamycin-mode-of-action
#5
Jonna K Hakulinen, Jenny Hering, Gisela Brändén, Hongming Chen, Arjan Snijder, Margareta Ek, Patrik Johansson
The rapid increase of antibiotic resistance has created an urgent need to develop novel antimicrobial agents. Here we describe the crystal structure of the promising bacterial target phospho-N-acetylmuramoyl-pentapeptide translocase (MraY) in complex with the nucleoside antibiotic tunicamycin. The structure not only reveals the mode of action of several related natural-product antibiotics but also gives an indication on the binding mode of the MraY UDP-MurNAc-pentapeptide and undecaprenyl-phosphate substrates...
January 9, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28068311/structural-and-functional-insights-into-asymmetric-enzymatic-dehydration-of-alkenols
#6
Bettina M Nestl, Christopher Geinitz, Stephanie Popa, Sari Rizek, Robert J Haselbeck, Rosary Stephen, Michael A Noble, Max-Philipp Fischer, Erik C Ralph, Hoi Ting Hau, Henry Man, Muhiadin Omar, Johan P Turkenburg, Stephen van Dien, Stephanie J Culler, Gideon Grogan, Bernhard Hauer
The asymmetric dehydration of alcohols is an important process for the direct synthesis of alkenes. We report the structure and substrate specificity of the bifunctional linalool dehydratase isomerase (LinD) from the bacterium Castellaniella defragrans that catalyzes in nature the hydration of β-myrcene to linalool and the subsequent isomerization to geraniol. Enzymatic kinetic resolutions of truncated and elongated aromatic and aliphatic tertiary alcohols (C5-C15) that contain a specific signature motif demonstrate the broad substrate specificity of LinD...
January 9, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28068310/visualizing-the-secondary-and-tertiary-architectural-domains-of-lncrna-repa
#7
Fei Liu, Srinivas Somarowthu, Anna Marie Pyle
Long noncoding RNAs (lncRNAs) are important for gene expression, but little is known about their structures. RepA is a 1.6-kb mouse lncRNA comprising the same sequence as the 5' region of Xist, including A and F repeats. It has been proposed to facilitate the initiation and spread of X-chromosome inactivation, although its exact role is poorly understood. To gain insight into the molecular mechanism of RepA and Xist, we determined a complete phylogenetically validated secondary-structural map of RepA through SHAPE and DMS chemical probing of a homogeneously folded RNA in vitro...
January 9, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28068309/biomimetic-spinning-of-artificial-spider-silk-from-a-chimeric-minispidroin
#8
Marlene Andersson, Qiupin Jia, Ana Abella, Xiau-Yeen Lee, Michael Landreh, Pasi Purhonen, Hans Hebert, Maria Tenje, Carol V Robinson, Qing Meng, Gustavo R Plaza, Jan Johansson, Anna Rising
Herein we present a chimeric recombinant spider silk protein (spidroin) whose aqueous solubility equals that of native spider silk dope and a spinning device that is based solely on aqueous buffers, shear forces and lowered pH. The process recapitulates the complex molecular mechanisms that dictate native spider silk spinning and is highly efficient; spidroin from one liter of bacterial shake-flask culture is enough to spin a kilometer of the hitherto toughest as-spun artificial spider silk fiber.
January 9, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28024151/%C3%AE-2-adrenergic-receptor-control-of-endosomal-pth-receptor-signaling-via-g%C3%AE-%C3%AE
#9
Frédéric G Jean-Alphonse, Vanessa L Wehbi, Jingming Chen, Masaki Noda, Juan M Taboas, Kunhong Xiao, Jean-Pierre Vilardaga
Cells express several G-protein-coupled receptors (GPCRs) at their surfaces, transmitting simultaneous extracellular hormonal and chemical signals into cells. A comprehensive understanding of mechanisms underlying the integrated signaling response induced by distinct GPCRs is thus required. Here we found that the β2-adrenergic receptor, which induces a short cAMP response, prolongs nuclear cAMP and protein kinase A (PKA) activation by promoting endosomal cAMP production in parathyroid hormone (PTH) receptor signaling through the stimulatory action of G protein Gβγ subunits on adenylate cyclase type 2...
December 26, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/28024150/orthogonal-lipid-sensors-identify-transbilayer-asymmetry-of-plasma-membrane-cholesterol
#10
Shu-Lin Liu, Ren Sheng, Jae Hun Jung, Li Wang, Ewa Stec, Matthew J O'Connor, Seohyoen Song, Rama Kamesh Bikkavilli, Robert A Winn, Daesung Lee, Kwanghee Baek, Kazumitsu Ueda, Irena Levitan, Kwang-Pyo Kim, Wonhwa Cho
Controlled distribution of lipids across various cell membranes is crucial for cell homeostasis and regulation. We developed an imaging method that allows simultaneous in situ quantification of cholesterol in two leaflets of the plasma membrane (PM) using tunable orthogonal cholesterol sensors. Our imaging revealed marked transbilayer asymmetry of PM cholesterol (TAPMC) in various mammalian cells, with the concentration in the inner leaflet (IPM) being ∼12-fold lower than that in the outer leaflet (OPM). The asymmetry was maintained by active transport of cholesterol from IPM to OPM and its chemical retention at OPM...
December 26, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27992882/orphan-receptor-ligand-discovery-by-pickpocketing-pharmacological-neighbors
#11
Tony Ngo, Andrey V Ilatovskiy, Alastair G Stewart, James L J Coleman, Fiona M McRobb, R Peter Riek, Robert M Graham, Ruben Abagyan, Irina Kufareva, Nicola J Smith
Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor-ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand-residue interactions observed in crystallographically characterized GPCRs...
December 19, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27992881/molecular-insights-into-the-enzyme-promiscuity-of-an-aromatic-prenyltransferase
#12
Ridao Chen, Bingquan Gao, Xiao Liu, Feiying Ruan, Yong Zhang, Jizhong Lou, Keping Feng, Carsten Wunsch, Shu-Ming Li, Jungui Dai, Fei Sun
Aromatic prenyltransferases (aPTases) transfer prenyl moieties from isoprenoid donors to various aromatic acceptors, some of which have the rare property of extreme enzymatic promiscuity toward both a variety of prenyl donors and a large diversity of acceptors. In this study, we discovered a new aPTase, AtaPT, from Aspergillus terreus that exhibits unprecedented promiscuity toward diverse aromatic acceptors and prenyl donors and also yields products with a range of prenylation patterns. Systematic crystallographic studies revealed various discrete conformations for ligand binding with donor-dependent acceptor specificity and multiple binding sites within a spacious hydrophobic substrate-binding pocket...
December 19, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27992880/a-fluorescent-probe-for-cysteine-depalmitoylation-reveals-dynamic-apt-signaling
#13
Rahul S Kathayat, Pablo D Elvira, Bryan C Dickinson
Hundreds of human proteins are modified by reversible palmitoylation of cysteine residues (S-palmitoylation), but the regulation of depalmitoylation is poorly understood. Here, we develop 'depalmitoylation probes' (DPPs), small-molecule fluorophores, to monitor the endogenous activity levels of 'erasers' of S-palmitoylation, acylprotein thioesterases (APTs). Live-cell analysis with DPPs reveals rapid growth-factor-mediated inhibition of the depalmitoylation activity of APTs, exposing a novel regulatory mechanism of dynamic lipid signaling...
December 19, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27992879/inhibitors-of-mycobacterium-tuberculosis-dosrst-signaling-and-persistence
#14
Huiqing Zheng, Christopher J Colvin, Benjamin K Johnson, Paul D Kirchhoff, Michael Wilson, Katriana Jorgensen-Muga, Scott D Larsen, Robert B Abramovitch
The Mycobacterium tuberculosis (Mtb) DosRST two-component regulatory system promotes the survival of Mtb during non-replicating persistence (NRP). NRP bacteria help drive the long course of tuberculosis therapy; therefore, chemical inhibition of DosRST may inhibit the ability of Mtb to establish persistence and thus shorten treatment. Using a DosRST-dependent fluorescent Mtb reporter strain, a whole-cell phenotypic high-throughput screen of a ∼540,000 compound small-molecule library was conducted. The screen discovered novel inhibitors of the DosRST regulon, including three compounds that were subject to follow-up studies: artemisinin, HC102A and HC103A...
December 19, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27941760/precise-small-molecule-recognition-of-a-toxic-cug-rna-repeat-expansion
#15
Suzanne G Rzuczek, Lesley A Colgan, Yoshio Nakai, Michael D Cameron, Denis Furling, Ryohei Yasuda, Matthew D Disney
Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)(exp)) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis...
December 12, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27941759/rewiring-human-cellular-input-output-using-modular-extracellular-sensors
#16
Kelly A Schwarz, Nichole M Daringer, Taylor B Dolberg, Joshua N Leonard
Engineered cell-based therapies comprise a promising emerging strategy for treating diverse diseases. Realizing this promise requires new tools for engineering cells to sense and respond to soluble extracellular factors, which provide information about both physiological state and the local environment. Here, we report such a biosensor engineering strategy, leveraging a self-contained receptor-signal transduction system termed modular extracellular sensor architecture (MESA). We developed MESA receptors that enable cells to sense vascular endothelial growth factor (VEGF) and, in response, secrete interleukin 2 (IL-2)...
December 12, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27941758/single-molecule-analysis-reveals-multi-state-folding-of-a-guanine-riboswitch
#17
Vishnu Chandra, Zain Hannan, Huizhong Xu, Maumita Mandal
Guanine-responsive riboswitches undergo ligand-dependent structural rearrangements to control gene expression by transcription termination. While the molecular basis for ligand recognition is well established, the associated structural rearrangements and the kinetics involved in the formation of the aptamer domain are less well understood. Using high-resolution optical tweezers, we followed the folding trajectories of a single molecule of the xpt-pbuX guanine aptamer from Bacillus subtilis. We report a rapid six-state conformational rearrangement, in which three of the states are guanine dependent, during the transition from the linear to the native receptor conformation...
December 12, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27918561/a-human-microprotein-that-interacts-with-the-mrna-decapping-complex
#18
Nadia G D'Lima, Jiao Ma, Lauren Winkler, Qian Chu, Ken H Loh, Elizabeth O Corpuz, Bogdan A Budnik, Jens Lykke-Andersen, Alan Saghatelian, Sarah A Slavoff
Proteomic detection of non-annotated microproteins indicates the translation of hundreds of small open reading frames (smORFs) in human cells, but whether these microproteins are functional or not is unknown. Here, we report the discovery and characterization of a 7-kDa human microprotein we named non-annotated P-body dissociating polypeptide (NoBody). NoBody interacts with mRNA decapping proteins, which remove the 5' cap from mRNAs to promote 5'-to-3' decay. Decapping proteins participate in mRNA turnover and nonsense-mediated decay (NMD)...
December 5, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27918560/genome-wide-chemical-mapping-of-o-glcnacylated-proteins-in-drosophila-melanogaster
#19
Ta-Wei Liu, Mike Myschyshyn, Donald A Sinclair, Samy Cecioni, Kevin Beja, Barry M Honda, Ryan D Morin, David J Vocadlo
N-Acetylglucosamine β-O-linked to nucleocytoplasmic proteins (O-GlcNAc) is implicated in the regulation of gene expression in organisms, from humans to Drosophila melanogaster. Within Drosophila, O-GlcNAc transferase (OGT) is one of the Polycomb group proteins (PcGs) that act through Polycomb group response elements (PREs) to silence homeotic (HOX) and other PcG target genes. Using Drosophila, we identify new O-GlcNAcylated PcG proteins and develop an antibody-free metabolic feeding approach to chemoselectively map genomic loci enriched in O-GlcNAc using next-generation sequencing...
December 5, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27918559/mutations-along-a-tet2-active-site-scaffold-stall-oxidation-at-5-hydroxymethylcytosine
#20
Monica Yun Liu, Hedieh Torabifard, Daniel J Crawford, Jamie E DeNizio, Xing-Jun Cao, Benjamin A Garcia, G Andrés Cisneros, Rahul M Kohli
Ten-eleven translocation (TET) enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) to yield 5-hydroxymethylcytosine (hmC) and the rarer bases 5-formylcytosine (fC) and 5-carboxylcytosine (caC). Stepwise oxidation obscures how each individual base forms and functions in epigenetic regulation, and prompts the question of whether TET enzymes primarily serve to generate hmC or are adapted to produce fC and caC as well. By mutating a single, conserved active site residue in human TET2, Thr1372, we uncovered enzyme variants that permit oxidation to hmC but largely eliminate fC and caC...
December 5, 2016: Nature Chemical Biology
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