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Nature Chemical Biology

Phillip A Lichtor, Zhen Chen, Nadine H Elowe, Jonathan C Chen, David R Liu
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...
February 11, 2019: Nature Chemical Biology
Agata Nawrotek, Sarah Benabdi, Supaporn Niyomchon, Marie-Hélène Kryszke, Christophe Ginestier, Tatiana Cañeque, Livia Tepshi, Angelica Mariani, Robert P St Onge, Guri Giaever, Corey Nislow, Emmanuelle Charafe-Jauffret, Raphaël Rodriguez, Mahel Zeghouf, Jacqueline Cherfils
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. We show that the small molecule Bragsin inhibits BRAG2-mediated Arf GTPase activation in vitro in a manner that requires a membrane...
February 11, 2019: Nature Chemical Biology
Honghui Ma, Xiaoyun Wang, Jiabin Cai, Qing Dai, S Kundhavai Natchiar, Ruitu Lv, Kai Chen, Zhike Lu, Hao Chen, Yujiang Geno Shi, Fei Lan, Jia Fan, Bruno P Klaholz, Tao Pan, Yang Shi, Chuan He
In the version of this article originally published, the references were incorrectly re-ordered during production. The hyphen in "N6 -methyladenosine" in the title was also superscript. The errors have been corrected in the HTML and PDF versions of the paper.
February 8, 2019: Nature Chemical Biology
Yeon Hee Ban, Myoung Chong Song, Jae-Yeon Hwang, Hea-Lyung Shin, Hak Joong Kim, Seung Kon Hong, Na Joon Lee, Je Won Park, Sun-Shin Cha, Hung-Wen Liu, Yeo Joon Yoon
In the version of this article originally published, reference to another structure of GenB1 was omitted (Dow, G. T., Thoden, J. B., & Holden, H. M. The three-dimensional structure of NeoB: an aminotransferase involved in the biosynthesis of neomycin. Protein Sci. 27, 945-956 (2018)). This paper is now cited as reference 32, and "Another structure of GenB1 was also reported independently during the revision of this article32 " was added to the text in the Discussion section. This error has been corrected in the PDF and HTML versions of the article...
February 6, 2019: Nature Chemical Biology
Thomas P Garner, Dulguun Amgalan, Denis E Reyna, Sheng Li, Richard N Kitsis, Evripidis Gavathiotis
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. Here, we describe a class of small-molecule BAX inhibitors, termed BAIs, that bind directly to a previously unrecognized pocket and allosterically inhibit BAX activation...
February 4, 2019: Nature Chemical Biology
Gangadhara Gangadhara, Göran Dahl, Thomas Bohnacker, Rebecca Rae, Jenny Gunnarsson, Stefan Blaho, Linda Öster, Helena Lindmark, Kostas Karabelas, Nils Pemberton, Christian Tyrchan, Mickael Mogemark, Matthias P Wymann, Roger L Williams, Matthew W D Perry, Tineke Papavoine, Jens Petersen
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...
February 4, 2019: Nature Chemical Biology
Dukas Jurėnas, Laurence Van Melderen, Abel Garcia-Pino
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 RNAfMet . In the repressor complex, AtaR intrinsically disordered region interacts with AtaT at two different sites, folding into different structures, that are involved in two separate functional roles, toxin neutralization and placing the DNA-binding domains of AtaR in a binding-compatible orientation...
February 4, 2019: Nature Chemical Biology
Rhushikesh A Kulkarni, Daniel W Bak, Darmood Wei, Sarah E Bergholtz, Chloe A Briney, Jonathan H Shrimp, Aktan Alpsoy, Abigail L Thorpe, Arissa E Bavari, Daniel R Crooks, Michaella Levy, Laurence Florens, Michael P Washburn, Norma Frizzell, Emily C Dykhuizen, Eranthie Weerapana, W Marston Linehan, Jordan L Meier
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). We applied a fumarate-competitive chemoproteomic probe in concert with LC-MS/MS to discover new cysteines sensitive to fumarate hydratase (FH) mutation in HLRCC cell models...
February 4, 2019: Nature Chemical Biology
Jean Quancard, Theo Klein, Shan-Yu Fung, Martin Renatus, Nicola Hughes, Laura Israël, John J Priatel, Sohyeong Kang, Michael A Blank, Rosa I Viner, Jutta Blank, Achim Schlapbach, Paul Erbel, Jayachandran Kizhakkedathu, Frédéric Villard, René Hersperger, Stuart E Turvey, Joerg Eder, Frédéric Bornancin, Christopher M Overall
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. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions...
January 28, 2019: Nature Chemical Biology
Christian Schmidl, Gregory I Vladimer, André F Rendeiro, Susanne Schnabl, Thomas Krausgruber, Christina Taubert, Nikolaus Krall, Tea Pemovska, Mohammad Araghi, Berend Snijder, Rainer Hubmann, Anna Ringler, Kathrin Runggatscher, Dita Demirtas, Oscar Lopez de la Fuente, Martin Hilgarth, Cathrin Skrabs, Edit Porpaczy, Michaela Gruber, Gregor Hoermann, Stefan Kubicek, Philipp B Staber, Medhat Shehata, Giulio Superti-Furga, Ulrich Jäger, Christoph Bock
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...
January 28, 2019: Nature Chemical Biology
Deenah Osman, Maria Alessandra Martini, Andrew W Foster, Junjun Chen, Andrew J P Scott, Richard J Morton, Jonathan W Steed, Elena Lurie-Luke, Thomas G Huggins, Andrew D Lawrence, Evelyne Deery, Martin J Warren, Peter T Chivers, Nigel J Robinson
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. Metal-sensing transcriptional regulators are tuned to the intracellular availabilities of their cognate ions. Here we have determined the standard free energy for metal complex formation to which each sensor, in a set of bacterial metal sensors, is attuned: the less competitive the metal, the less favorable the free energy and hence the greater availability to which the cognate allosteric mechanism is tuned...
January 28, 2019: Nature Chemical Biology
Xiaoxue Zhou, Frances P Rodriguez-Rivera, Hoong Chuin Lim, Jason C Bell, Thomas G Bernhardt, Carolyn R Bertozzi, Julie A Theriot
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. Additionally, we demonstrate that in C...
January 21, 2019: Nature Chemical Biology
Ruobo Zhou, Olivia Yang, Anne-Cécile Déclais, Hyeonseok Jin, Gwang Hyeon Gwon, Alasdair D J Freeman, Yunje Cho, David M J Lilley, Taekjip Ha
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. Single-molecule fluorescence resonance energy transfer analysis of resolving enzymes from bacteriophages (T7 endonuclease I), bacteria (RuvC), fungi (GEN1) and humans (hMus81-Eme1) showed that both types of HJ dynamics still occur after enzyme binding...
January 21, 2019: Nature Chemical Biology
Ulrich Rass
No abstract text is available yet for this article.
January 21, 2019: Nature Chemical Biology
Naoya Shindo, Hirokazu Fuchida, Mami Sato, Kosuke Watari, Tomohiro Shibata, Keiko Kuwata, Chizuru Miura, Kei Okamoto, Yuji Hatsuyama, Keisuke Tokunaga, Seiichi Sakamoto, Satoshi Morimoto, Yoshito Abe, Mitsunori Shiroishi, Jose M M Caaveiro, Tadashi Ueda, Tomonori Tamura, Naoya Matsunaga, Takaharu Nakao, Satoru Koyanagi, Shigehiro Ohdo, Yasuchika Yamaguchi, Itaru Hamachi, Mayumi Ono, Akio Ojida
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). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0...
January 14, 2019: Nature Chemical Biology
Dhanashree S Kelkar, Govindan Ravikumar, Neelay Mehendale, Shubham Singh, Alaumy Joshi, Ajay Kumar Sharma, Amol Mhetre, Abinaya Rajendran, Harinath Chakrapani, Siddhesh S Kamat
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. Here, we report a small molecule that generates ROS in different mammalian cells...
January 14, 2019: Nature Chemical Biology
Jennifer S Spence, Ruina He, Hans-Heinrich Hoffmann, Tandrila Das, Emmanuelle Thinon, Charles M Rice, Tao Peng, Kartik Chandran, Howard C Hang
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...
January 14, 2019: Nature Chemical Biology
Erin Nolin, Sara Gans, Luis Llamas, Somnath Bandyopadhyay, Scott M Brittain, Paula Bernasconi-Elias, Kyle P Carter, Joseph J Loureiro, Jason R Thomas, Markus Schirle, Yi Yang, Ning Guo, Guglielmo Roma, Sven Schuierer, Martin Beibel, Alicia Lindeman, Frederic Sigoillot, Amy Chen, Kevin X Xie, Samuel Ho, John Reece-Hoyes, Wilhelm A Weihofen, Kayla Tyskiewicz, Dominic Hoepfner, Richard I McDonald, Nicolette Guthrie, Abhishek Dogra, Haibing Guo, Jian Shao, Jian Ding, Stephen M Canham, Geoff Boynton, Elizabeth L George, Zhao B Kang, Christophe Antczak, Jeffery A Porter, Owen Wallace, John A Tallarico, Amy E Palmer, Jeremy L Jenkins, Rishi K Jain, Simon M Bushell, Christy J Fryer
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...
January 14, 2019: Nature Chemical Biology
Yeon Hee Ban, Myoung Chong Song, Jae-Yeon Hwang, Hea-Lyung Shin, Hak Joong Kim, Seung Kon Hong, Na Joon Lee, Je Won Park, Sun-Shin Cha, Hung-Wen Liu, Yeo Joon Yoon
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. The narrow substrate specificity of a key glycosyltransferase and the C6'-amination enzymes, in combination with the weak and unsynchronized gene expression of the 2'-deamination enzymes, limits GB production in M...
January 14, 2019: Nature Chemical Biology
Michaela TerAvest
No abstract text is available yet for this article.
January 14, 2019: Nature Chemical Biology
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