2,690 results match your criteria Nature Chemical Biology [Journal]


Site-specific ubiquitylation and SUMOylation using genetic-code expansion and sortase.

Nat Chem Biol 2019 Mar 15;15(3):276-284. Epub 2019 Feb 15.

Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Lab for Synthetic Biochemistry, Technical University of Munich, Institute for Advanced Study, TUM-IAS, Garching, Germany.

Post-translational modification of proteins with ubiquitin and ubiquitin-like proteins (Ubls) is central to the regulation of eukaryotic cellular processes. Our ability to study the effects of ubiquitylation, however, is limited by the difficulty to prepare homogenously modified proteins in vitro and by the impossibility to selectively trigger specific ubiquitylation events in living cells. Here we combine genetic-code expansion, bioorthogonal Staudinger reduction and sortase-mediated transpeptidation to develop a general tool to ubiquitylate proteins in an inducible fashion. Read More

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http://dx.doi.org/10.1038/s41589-019-0227-4DOI Listing
March 2019
12.996 Impact Factor

HIV seals an envelope.

Authors:
Mirella Bucci

Nat Chem Biol 2019 Mar;15(3):207

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-019-0238-1DOI Listing

To be or not to be?

Authors:
Yiyun Song

Nat Chem Biol 2019 Mar;15(3):207

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-019-0239-0DOI Listing

A super-powered S-layer.

Authors:
Caitlin Deane

Nat Chem Biol 2019 Mar;15(3):207

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-019-0236-3DOI Listing

METTLing with translation.

Authors:
Grant Miura

Nat Chem Biol 2019 Mar;15(3):207

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-019-0237-2DOI Listing

Decoding without the cipher.

Nat Chem Biol 2019 Mar;15(3):210-212

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.

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http://dx.doi.org/10.1038/s41589-019-0230-9DOI Listing

Snappy cell division in Actinobacteria.

Authors:
Martin S Pavelka

Nat Chem Biol 2019 Mar;15(3):208-209

Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

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http://dx.doi.org/10.1038/s41589-019-0226-5DOI Listing

Side chain determinants of biopolymer function during selection and replication.

Nat Chem Biol 2019 Feb 11. Epub 2019 Feb 11.

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

The chemical functionalities within biopolymers determine their physical properties and biological activities. The relationship between the side chains available to a biopolymer population and the potential functions of the resulting polymers, however, has proven difficult to study experimentally. Using seven sets of chemically diverse charged, polar, and nonpolar side chains, we performed cycles of artificial translation, in vitro selections for binding to either PCSK9 or IL-6 protein, and replication on libraries of random side chain-functionalized nucleic acid polymers. Read More

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http://dx.doi.org/10.1038/s41589-019-0229-2DOI Listing
February 2019
12.996 Impact Factor

PH-domain-binding inhibitors of nucleotide exchange factor BRAG2 disrupt Arf GTPase signaling.

Nat Chem Biol 2019 Feb 11. Epub 2019 Feb 11.

Laboratoire de Biologie et Pharmacologie Appliquée, Ecole normale supérieure Paris-Saclay, Cachan, France.

Peripheral membrane proteins orchestrate many physiological and pathological processes, making regulation of their activities by small molecules highly desirable. However, they are often refractory to classical competitive inhibition. Here, we demonstrate that potent and selective inhibition of peripheral membrane proteins can be achieved by small molecules that target protein-membrane interactions by a noncompetitive mechanism. Read More

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http://dx.doi.org/10.1038/s41589-019-0228-3DOI Listing
February 2019

Publisher Correction: N-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation.

Nat Chem Biol 2019 Feb 8. Epub 2019 Feb 8.

Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.

In the version of this article originally published, the references were incorrectly re-ordered during production. The hyphen in "N-methyladenosine" in the title was also superscript. The errors have been corrected in the HTML and PDF versions of the paper. Read More

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http://dx.doi.org/10.1038/s41589-019-0233-6DOI Listing
February 2019

Author Correction: Complete reconstitution of the diverse pathways of gentamicin B biosynthesis.

Nat Chem Biol 2019 Feb 6. Epub 2019 Feb 6.

Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, Republic of Korea.

In the version of this article originally published, reference to another structure of GenB1 was omitted (Dow, G. T., Thoden, J. Read More

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http://dx.doi.org/10.1038/s41589-019-0232-7DOI Listing
February 2019
12.996 Impact Factor

Small-molecule allosteric inhibitors of BAX.

Nat Chem Biol 2019 Feb 4. Epub 2019 Feb 4.

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.

BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Upon binding by BH3-only proteins, cytosolic BAX undergoes conformational activation and translocation, resulting in mitochondrial outer-membrane permeabilization. Efforts to rationally target BAX and develop inhibitors have been elusive, despite the clear therapeutic potential of inhibiting BAX-mediated cell death in a host of diseases. Read More

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http://dx.doi.org/10.1038/s41589-018-0223-0DOI Listing
February 2019

A class of highly selective inhibitors bind to an active state of PI3Kγ.

Nat Chem Biol 2019 Feb 4. Epub 2019 Feb 4.

Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

We have discovered a class of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kβ. On the basis of X-ray crystallography, hydrogen-deuterium exchange-mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kγ. Site directed mutagenesis explained how the conformational changes occur. Read More

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http://dx.doi.org/10.1038/s41589-018-0215-0DOI Listing
February 2019

Mechanism of regulation and neutralization of the AtaR-AtaT toxin-antitoxin system.

Nat Chem Biol 2019 Mar 4;15(3):285-294. Epub 2019 Feb 4.

Cellular and Molecular Microbiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.

GCN5-related N-acetyl-transferase (GNAT)-like enzymes from toxin-antitoxin modules are strong inhibitors of protein synthesis. Here, we present the bases of the regulatory mechanisms of ataRT, a model GNAT-toxin-antitoxin module, from toxin synthesis to its action as a transcriptional de-repressor. We show the antitoxin (AtaR) traps the toxin (AtaT) in a pre-catalytic monomeric state and precludes the effective binding of ac-CoA and its target Met-transfer RNA. Read More

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http://www.nature.com/articles/s41589-018-0216-z
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http://dx.doi.org/10.1038/s41589-018-0216-zDOI Listing
March 2019
5 Reads

A chemoproteomic portrait of the oncometabolite fumarate.

Nat Chem Biol 2019 Feb 4. Epub 2019 Feb 4.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MA, USA.

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Read More

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http://dx.doi.org/10.1038/s41589-018-0217-yDOI Listing
February 2019
1 Read

An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.

Nat Chem Biol 2019 Mar 28;15(3):304-313. Epub 2019 Jan 28.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. Read More

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http://dx.doi.org/10.1038/s41589-018-0222-1DOI Listing

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL.

Nat Chem Biol 2019 Mar 28;15(3):232-240. Epub 2019 Jan 28.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. Read More

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http://www.nature.com/articles/s41589-018-0205-2
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http://dx.doi.org/10.1038/s41589-018-0205-2DOI Listing
March 2019
12 Reads

Bacterial sensors define intracellular free energies for correct enzyme metalation.

Nat Chem Biol 2019 Mar 28;15(3):241-249. Epub 2019 Jan 28.

Department of Biosciences, Durham University, Durham, UK.

There is a challenge for metalloenzymes to acquire their correct metals because some inorganic elements form more stable complexes with proteins than do others. These preferences can be overcome provided some metals are more available than others. However, while the total amount of cellular metal can be readily measured, the available levels of each metal have been more difficult to define. Read More

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http://dx.doi.org/10.1038/s41589-018-0211-4DOI Listing

Sequential assembly of the septal cell envelope prior to V snapping in Corynebacterium glutamicum.

Nat Chem Biol 2019 Mar 21;15(3):221-231. Epub 2019 Jan 21.

Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.

Members of the Corynebacterineae, including Corynebacterium and Mycobacterium, have an atypical cell envelope characterized by an additional mycomembrane outside of the peptidoglycan layer. How this multilayered cell envelope is assembled remains unclear. Here, we tracked the assembly dynamics of different envelope layers in Corynebacterium glutamicum and Mycobacterium smegmatis by using metabolic labeling and found that the septal cell envelope is assembled sequentially in both species. Read More

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http://dx.doi.org/10.1038/s41589-018-0206-1DOI Listing
March 2019
1 Read

Junction resolving enzymes use multivalency to keep the Holliday junction dynamic.

Nat Chem Biol 2019 Mar 21;15(3):269-275. Epub 2019 Jan 21.

Department of Physics and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Champaign, IL, USA.

Holliday junction (HJ) resolution by resolving enzymes is essential for chromosome segregation and recombination-mediated DNA repair. HJs undergo two types of structural dynamics that determine the outcome of recombination: conformer exchange between two isoforms and branch migration. However, it is unknown how the preferred branch point and conformer are achieved between enzyme binding and HJ resolution given the extensive binding interactions seen in static crystal structures. Read More

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http://dx.doi.org/10.1038/s41589-018-0209-yDOI Listing
March 2019
1 Read

Freedom of movement.

Authors:
Ulrich Rass

Nat Chem Biol 2019 Mar;15(3):209-210

Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK.

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http://dx.doi.org/10.1038/s41589-019-0224-7DOI Listing
March 2019
1 Read

Molecular tools for imaging and recording neuronal activity.

Nat Chem Biol 2019 Feb 18;15(2):101-110. Epub 2019 Jan 18.

Departments of Genetics, Biology, and Chemistry, Stanford University, Stanford, CA, USA.

To understand how the brain relates to behavior, it is essential to record neural activity in awake, behaving animals. To achieve this goal, a large variety of genetically encoded sensors have been developed to monitor and record the series of events following neuronal firing, including action potentials, intracellular calcium rise, neurotransmitter release and immediate early gene expression. In this Review, we discuss the existing genetically encoded tools for detecting and integrating neuronal activity in animals and highlight the remaining challenges and future opportunities for molecular biologists. Read More

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http://dx.doi.org/10.1038/s41589-018-0207-0DOI Listing
February 2019

Pass it along.

Authors:
Yiyun Song

Nat Chem Biol 2019 Feb;15(2):95

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-018-0221-2DOI Listing
February 2019

Ras tuning.

Authors:
Grant Miura

Nat Chem Biol 2019 Feb;15(2):95

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-018-0219-9DOI Listing
February 2019

A new Tar-get for inhibition.

Authors:
Mirella Bucci

Nat Chem Biol 2019 Feb;15(2):95

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-018-0220-3DOI Listing
February 2019

Cutting in choline.

Authors:
Caitlin Deane

Nat Chem Biol 2019 Feb;15(2):95

Nature Chemical Biology, .

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http://dx.doi.org/10.1038/s41589-018-0218-xDOI Listing
February 2019

Selective and reversible modification of kinase cysteines with chlorofluoroacetamides.

Nat Chem Biol 2019 Mar 14;15(3):250-258. Epub 2019 Jan 14.

Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). Read More

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http://dx.doi.org/10.1038/s41589-018-0204-3DOI Listing

A chemical-genetic screen identifies ABHD12 as an oxidized-phosphatidylserine lipase.

Nat Chem Biol 2019 Feb 14;15(2):169-178. Epub 2019 Jan 14.

Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, India.

Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, oxidative stress results, in which excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a proapoptotic 'eat me' signal, is produced in response to elevated ROS, yet little is known regarding its chemical composition and metabolism. Read More

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http://www.nature.com/articles/s41589-018-0195-0
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http://dx.doi.org/10.1038/s41589-018-0195-0DOI Listing
February 2019
5 Reads
12.996 Impact Factor

IFITM3 directly engages and shuttles incoming virus particles to lysosomes.

Nat Chem Biol 2019 Mar 14;15(3):259-268. Epub 2019 Jan 14.

Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, NY, USA.

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) have emerged as important innate immune effectors that prevent diverse virus infections in vertebrates. However, the cellular mechanisms and live-cell imaging of these small membrane proteins have been challenging to evaluate during viral entry of mammalian cells. Using CRISPR-Cas9-mediated IFITM-mutant cell lines, we demonstrate that human IFITM1, IFITM2 and IFITM3 act cooperatively and function in a dose-dependent fashion in interferon-stimulated cells. Read More

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http://dx.doi.org/10.1038/s41589-018-0213-2DOI Listing

Discovery of a ZIP7 inhibitor from a Notch pathway screen.

Nat Chem Biol 2019 Feb 14;15(2):179-188. Epub 2019 Jan 14.

Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Read More

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http://www.nature.com/articles/s41589-018-0200-7
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http://dx.doi.org/10.1038/s41589-018-0200-7DOI Listing
February 2019
11 Reads

Complete reconstitution of the diverse pathways of gentamicin B biosynthesis.

Nat Chem Biol 2019 Mar 14;15(3):295-303. Epub 2019 Jan 14.

Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, Republic of Korea.

Gentamicin B (GB), a valuable starting material for the preparation of the semisynthetic aminoglycoside antibiotic isepamicin, is produced in trace amounts by the wild-type Micromonospora echinospora. Though the biosynthetic pathway to GB has remained obscure for decades, we have now identified three hidden pathways to GB production via seven hitherto unknown intermediates in M. echinospora. Read More

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http://www.nature.com/articles/s41589-018-0203-4
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http://dx.doi.org/10.1038/s41589-018-0203-4DOI Listing
March 2019
11 Reads
12.996 Impact Factor

Fast bioelectrical switches.

Nat Chem Biol 2019 Feb;15(2):99-100

Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.

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http://dx.doi.org/10.1038/s41589-018-0212-3DOI Listing
February 2019

A genetics-free method for high-throughput discovery of cryptic microbial metabolites.

Nat Chem Biol 2019 Feb 7;15(2):161-168. Epub 2019 Jan 7.

Department of Chemistry, Princeton University, Princeton, NJ, USA.

Bacteria contain an immense untapped trove of novel secondary metabolites in the form of 'silent' biosynthetic gene clusters (BGCs). These can be identified bioinformatically but are not expressed under normal laboratory growth conditions. Methods to access their products would dramatically expand the pool of bioactive compounds. Read More

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http://dx.doi.org/10.1038/s41589-018-0193-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339573PMC
February 2019
12.996 Impact Factor

Legionella effector SetA as a general O-glucosyltransferase for eukaryotic proteins.

Nat Chem Biol 2019 Mar 7;15(3):213-216. Epub 2019 Jan 7.

College of Chemistry and Molecular Engineering, Peking University, Beijing, China.

The identification of host protein substrates is key to understanding effector glycosyltransferases secreted by pathogenic bacteria and to using them for glycoprotein engineering. Here we report a chemical method for tagging, enrichment, and site-specific proteomic profiling of effector-modified proteins in host cells. Using this method, we discover that Legionella effector SetA α-O-glucosylates various eukaryotic proteins by recognizing a S/T-X-L-P/G sequence motif, which can be exploited to site-specifically introduce O-glucose on recombinant proteins. Read More

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http://www.nature.com/articles/s41589-018-0189-y
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http://dx.doi.org/10.1038/s41589-018-0189-yDOI Listing
March 2019
11 Reads

Protein circuits reprogram cells.

Nat Chem Biol 2019 Feb;15(2):96-97

Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1038/s41589-018-0210-5DOI Listing
February 2019

Targeted delivery of nitric oxide via a 'bump-and-hole'-based enzyme-prodrug pair.

Nat Chem Biol 2019 Feb 31;15(2):151-160. Epub 2018 Dec 31.

State key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Science, Nankai University, Tianjin, China.

The spatiotemporal generation of nitric oxide (NO), a versatile endogenous messenger, is precisely controlled. Despite its therapeutic potential for a wide range of diseases, NO-based therapies are limited clinically due to a lack of effective strategies for precisely delivering NO to a specific site. In the present study, we developed a novel NO delivery system via modification of an enzyme-prodrug pair of galactosidase-galactosyl-NONOate using a 'bump-and-hole' strategy. Read More

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http://dx.doi.org/10.1038/s41589-018-0190-5DOI Listing
February 2019
7 Reads

Activation of silent biosynthetic gene clusters using transcription factor decoys.

Nat Chem Biol 2019 Feb 31;15(2):111-114. Epub 2018 Dec 31.

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Here we report a transcription factor decoy strategy for targeted activation of eight large silent polyketide synthase and non-ribosomal peptide synthetase gene clusters, ranging from 50 to 134 kilobases (kb) in multiple streptomycetes, and characterization of a novel oxazole family compound produced by a 98-kb biosynthetic gene cluster. Owing to its simplicity and ease of use, this strategy can be scaled up readily for discovery of natural products in streptomycetes. Read More

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http://dx.doi.org/10.1038/s41589-018-0187-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339570PMC
February 2019

Noncanonical CTD kinases regulate RNA polymerase II in a gene-class-specific manner.

Nat Chem Biol 2019 Feb 31;15(2):123-131. Epub 2018 Dec 31.

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.

Phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) governs stage-specific interactions with different cellular machines. The CTD consists of YSPTSPS heptad repeats and sequential phosphorylations of Ser7, Ser5 and Ser2 occur universally at Pol II-transcribed genes. Phosphorylation of Thr4, however, appears to selectively modulate transcription of specific classes of genes. Read More

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http://dx.doi.org/10.1038/s41589-018-0194-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339578PMC
February 2019
2 Reads
12.996 Impact Factor

Conducting the CTD orchestra.

Nat Chem Biol 2019 Feb;15(2):97-98

Department of Functional Genomics and Cancer, IGBMC, Illkirch Graffenstaden, France.

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http://dx.doi.org/10.1038/s41589-018-0201-6DOI Listing
February 2019

Publisher Correction: Shared strategies for β-lactam catabolism in the soil microbiome.

Nat Chem Biol 2019 Feb;15(2):206

Department of Pathology and Immunology, Washington University in St Louis School of Medicine, Saint Louis, MO, USA.

In the version of the article originally published, the x axis of the graph in Fig. 4d was incorrectly labeled as "Retention time (min)". It should read "Reaction time (min)". Read More

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http://dx.doi.org/10.1038/s41589-018-0208-zDOI Listing
February 2019

Publisher Correction: Crystal structure of misoprostol bound to the labor inducer prostaglandin E receptor.

Nat Chem Biol 2019 Feb;15(2):206

Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA.

In the version of this article originally published, the present address for Petr Popov was incorrectly listed as 'Koltech Institute of Science & Technology, Moscow, Russia'. The correct present address is 'Skolkovo Institute of Science and Technology, Moscow, Russia'. The error has been corrected in the HTML and PDF versions of the paper. Read More

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http://www.nature.com/articles/s41589-018-0214-1
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http://dx.doi.org/10.1038/s41589-018-0214-1DOI Listing
February 2019
3 Reads

Affinity-based capture and identification of protein effectors of the growth regulator ppGpp.

Nat Chem Biol 2019 Feb 17;15(2):141-150. Epub 2018 Dec 17.

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

The nucleotide ppGpp is a highly conserved regulatory molecule in bacteria that helps tune growth rate to nutrient availability. Despite decades of study, how ppGpp regulates growth remains poorly understood. Here, we developed and validated a capture-compound mass spectrometry approach that identified >50 putative ppGpp targets in Escherichia coli. Read More

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http://dx.doi.org/10.1038/s41589-018-0183-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366861PMC
February 2019
12.996 Impact Factor

Metalloprotein switches that display chemical-dependent electron transfer in cells.

Nat Chem Biol 2019 Feb 17;15(2):189-195. Epub 2018 Dec 17.

Department of BioSciences, Rice University, Houston, TX, USA.

Biological electron transfer is challenging to directly regulate using environmental conditions. To enable dynamic, protein-level control over energy flow in metabolic systems for synthetic biology and bioelectronics, we created ferredoxin logic gates that utilize transcriptional and post-translational inputs to control energy flow through a synthetic electron transfer pathway that is required for bacterial growth. These logic gates were created by subjecting a thermostable, plant-type ferredoxin to backbone fission and fusing the resulting fragments to a pair of proteins that self-associate, a pair of proteins whose association is stabilized by a small molecule, and to the termini of a ligand-binding domain. Read More

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http://dx.doi.org/10.1038/s41589-018-0192-3DOI Listing
February 2019

Structural basis of 7SK RNA 5'-γ-phosphate methylation and retention by MePCE.

Nat Chem Biol 2019 Feb 17;15(2):132-140. Epub 2018 Dec 17.

Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.

Among RNA 5'-cap structures, γ-phosphate monomethylation is unique to a small subset of noncoding RNAs, 7SK and U6 in humans. 7SK is capped by methylphosphate capping enzyme (MePCE), which has a second nonenzymatic role as a core component of the 7SK ribonuclear protein (RNP), an essential regulator of RNA transcription. We report 2. Read More

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http://dx.doi.org/10.1038/s41589-018-0188-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339579PMC
February 2019

Riboregulated toehold-gated gRNA for programmable CRISPR-Cas9 function.

Nat Chem Biol 2019 Mar 10;15(3):217-220. Epub 2018 Dec 10.

Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA.

Predictable control over gene expression is essential to elicit desired synthetic cellular phenotypes. Although CRISPR-Cas9 offers a simple RNA-guided method for targeted transcriptional control, it lacks the ability to integrate endogenous cellular information for efficient signal processing. Here, we present a new class of riboregulators termed toehold-gated gRNA (thgRNA) by integrating toehold riboswitches into sgRNA scaffolds, and demonstrate their programmability for multiplexed regulation in Escherichia coli with minimal cross-talks. Read More

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http://www.nature.com/articles/s41589-018-0186-1
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March 2019
2 Reads

A DNA-based fluorescent reporter maps HOCl production in the maturing phagosome.

Nat Chem Biol 2018 Dec 10. Epub 2018 Dec 10.

Department of Chemistry, The University of Chicago, Chicago, IL, USA.

Phagocytes destroy pathogens by trapping them in a transient organelle called the phagosome, where they are bombarded with reactive oxygen species (ROS) and reactive nitrogen species (RNS). Imaging reactive species within the phagosome would directly reveal the chemical dynamics underlying pathogen destruction. Here we introduce a fluorescent, DNA-based combination reporter, cHOClate, which simultaneously images hypochlorous acid (HOCl) and pH quantitatively. Read More

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http://www.nature.com/articles/s41589-018-0176-3
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http://dx.doi.org/10.1038/s41589-018-0176-3DOI Listing
December 2018
22 Reads

Design of fast proteolysis-based signaling and logic circuits in mammalian cells.

Nat Chem Biol 2019 Feb 10;15(2):115-122. Epub 2018 Dec 10.

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia.

Cellular signal transduction is predominantly based on protein interactions and their post-translational modifications, which enable a fast response to input signals. Owing to difficulties in designing new unique protein-protein interactions, designed cellular logic has focused on transcriptional regulation; however, that process has a substantially slower response, because it requires transcription and translation. Here, we present de novo design of modular, scalable signaling pathways based on proteolysis and designed coiled coils (CC) and implemented in mammalian cells. Read More

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http://www.nature.com/articles/s41589-018-0181-6
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http://dx.doi.org/10.1038/s41589-018-0181-6DOI Listing
February 2019
8 Reads

NMethyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation.

Nat Chem Biol 2019 Jan 10;15(1):88-94. Epub 2018 Dec 10.

Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.

N-Methyladenosine (mA) RNA modification is present in messenger RNAs (mRNA), ribosomal RNAs (rRNA), and spliceosomal RNAs (snRNA) in humans. Although mRNA mA modifications have been extensively studied and shown to play critical roles in many cellular processes, the identity of mA methyltransferases for rRNAs and the function of rRNA mA modifications are unknown. Here we report a new mA methyltransferase, ZCCHC4, which primarily methylates human 28S rRNA and also interacts with a subset of mRNAs. Read More

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http://dx.doi.org/10.1038/s41589-018-0184-3DOI Listing
January 2019

Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis.

Nat Chem Biol 2019 Jan 10;15(1):71-79. Epub 2018 Dec 10.

The John Innes Centre, Department of Biological Chemistry, Norwich Research Park, Norwich, UK.

Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyzes the activation of its substrate 8-oxogeranial into a reactive enol intermediate, but does not catalyze the subsequent cyclization into nepetalactol. This discovery led us to identify a class of nepetalactol-related short-chain dehydrogenase enzymes (NEPS) from catmint (Nepeta mussinii) that capture this reactive intermediate and catalyze the stereoselective cyclisation into distinct nepetalactol stereoisomers. Read More

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http://www.nature.com/articles/s41589-018-0185-2
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http://dx.doi.org/10.1038/s41589-018-0185-2DOI Listing
January 2019
10 Reads

Beyond on or off.

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Nat Chem Biol 2019 Jan;15(1)

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http://dx.doi.org/10.1038/s41589-018-0202-5DOI Listing
January 2019