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Nature Chemical Biology

Daisuke Ogasawara, Taka-Aki Ichu, Vincent F Vartabedian, Jacqueline Benthuysen, Hui Jing, Alex Reed, Olesya A Ulanovskaya, Jonathan J Hulce, Amanda Roberts, Steven Brown, Hugh Rosen, John R Teijaro, Benjamin F Cravatt
ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12-/- mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12-/- mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function...
November 12, 2018: Nature Chemical Biology
Min Yang, Charlie Fehl, Karen V Lees, Eng-Kiat Lim, Wendy A Offen, Gideon J Davies, Dianna J Bowles, Matthew G Davidson, Stephen J Roberts, Benjamin G Davis
The elucidation and prediction of how changes in a protein result in altered activities and selectivities remain a major challenge in chemistry. Two hurdles have prevented accurate family-wide models: obtaining (i) diverse datasets and (ii) suitable parameter frameworks that encapsulate activities in large sets. Here, we show that a relatively small but broad activity dataset is sufficient to train algorithms for functional prediction over the entire glycosyltransferase superfamily 1 (GT1) of the plant Arabidopsis thaliana...
November 12, 2018: Nature Chemical Biology
Ryoji Suno, Sangbae Lee, Shoji Maeda, Satoshi Yasuda, Keitaro Yamashita, Kunio Hirata, Shoichiro Horita, Maki S Tawaramoto, Hirokazu Tsujimoto, Takeshi Murata, Masahiro Kinoshita, Masaki Yamamoto, Brian K Kobilka, Nagarajan Vaidehi, So Iwata, Takuya Kobayashi
Human muscarinic receptor M2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group...
November 12, 2018: Nature Chemical Biology
Jochen Schmid
No abstract text is available yet for this article.
November 12, 2018: Nature Chemical Biology
Huanbin Wang, Han Yao, Chushu Li, Hubing Shi, Jiang Lan, Zhaoli Li, Yao Zhang, Lunxi Liang, Jing-Yuan Fang, Jie Xu
Expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1) protects tumor cells from T cell-mediated immune surveillance, and immune checkpoint blockade (ICB) therapies targeting PD-1 and PD-L1 have exhibited significant clinical benefits. However, the relatively low response rate and observed ICB resistance highlight the need to understand the molecular regulation of PD-L1. Here we show that HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. HIP1R physically interacts with PD-L1 and delivers PD-L1 to the lysosome through a lysosomal targeting signal...
November 5, 2018: Nature Chemical Biology
Xin Li, Xiao-Meng Li, Yixiang Jiang, Zheng Liu, Yiwen Cui, Ka Yi Fung, Stan H E van der Beelen, Gaofei Tian, Liling Wan, Xiaobing Shi, C David Allis, Haitao Li, Yuanyuan Li, Xiang David Li
Chemical probes of epigenetic 'readers' of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in normal physiology and disease pathogenesis. Here we report the development of the first class of chemical probes of YEATS domains, newly identified 'readers' of histone lysine acetylation (Kac) and crotonylation (Kcr). Guided by the structural analysis of a YEATS-Kcr complex, we developed a series of peptide-based inhibitors of YEATS domains by targeting a unique π-π-π stacking interaction at the proteins' Kcr recognition site...
October 29, 2018: Nature Chemical Biology
Iria Bernhardsgrütter, Bastian Vögeli, Tristan Wagner, Dominik M Peter, Niña Socorro Cortina, Jörg Kahnt, Gert Bange, Sylvain Engilberge, Eric Girard, François Riobé, Olivier Maury, Seigo Shima, Jan Zarzycki, Tobias J Erb
Cells must cope with toxic or reactive intermediates formed during metabolism. One coping strategy is to sequester reactions that produce such intermediates within specialized compartments or tunnels connecting different active sites. Here, we show that propionyl-CoA synthase (PCS), an ∼ 400-kDa homodimer, three-domain fusion protein and the key enzyme of the 3-hydroxypropionate bi-cycle for CO2 fixation, sequesters its reactive intermediate acrylyl-CoA. Structural analysis showed that PCS forms a multicatalytic reaction chamber...
October 29, 2018: Nature Chemical Biology
Zhimin Huang, Junxing Zhao, Wei Deng, Yingyi Chen, Jialin Shang, Kun Song, Lu Zhang, Chengxiang Wang, Shaoyong Lu, Xiuyan Yang, Bin He, Jinrong Min, Hao Hu, Minjia Tan, Jianrong Xu, Qiufen Zhang, Jie Zhong, Xiaoxiang Sun, Zhiyong Mao, Houwen Lin, Mingzhe Xiao, Y Eugene Chin, Hualiang Jiang, Ying Xu, Guoqiang Chen, Jian Zhang
SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 Nε -acetyl-lysines 9 (H3K9ac) and 56 (H3K56ac). As a tumor suppressor, SIRT6 has frequently been found to have low expression in various cancers. Here, we report the identification of MDL-800, a selective SIRT6 activator. MDL-800 increased the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site; this interaction led to a global decrease in H3K9ac and H3K56ac levels in human hepatocellular carcinoma (HCC) cells...
October 29, 2018: Nature Chemical Biology
Olga Fedorova, G Erik Jagdmann, Rebecca L Adams, Lin Yuan, Michael C Van Zandt, Anna Marie Pyle
Specific RNA structures control numerous metabolic processes that impact human health, and yet efforts to target RNA structures de novo have been limited. In eukaryotes, the self-splicing group II intron is a mitochondrial RNA tertiary structure that is absent in vertebrates but essential for respiration in plants, fungi and yeast. Here we show that this RNA can be targeted through a process of high-throughput in vitro screening, SAR and lead optimization, resulting in high-affinity compounds that specifically inhibit group IIB intron splicing in vitro and in vivo and lack toxicity in human cells...
October 15, 2018: Nature Chemical Biology
James Palacino
No abstract text is available yet for this article.
October 15, 2018: Nature Chemical Biology
Takaaki Taniguchi, Kenjyo Miyauchi, Yuriko Sakaguchi, Seisuke Yamashita, Akiko Soma, Kozo Tomita, Tsutomu Suzuki
Modification of tRNA anticodons plays a critical role in ensuring accurate translation. N4 -acetylcytidine (ac4 C) is present at the anticodon first position (position 34) of bacterial elongator tRNAMet . Herein, we identified Bacillus subtilis ylbM (renamed tmcAL) as a novel gene responsible for ac4 C34 formation. Unlike general acetyltransferases that use acetyl-CoA, TmcAL activates an acetate ion to form acetyladenylate and then catalyzes ac4 C34 formation through a mechanism similar to tRNA aminoacylation...
August 27, 2018: Nature Chemical Biology
Matthieu Masureel, Yaozhong Zou, Louis-Philippe Picard, Emma van der Westhuizen, Jacob P Mahoney, João P G L M Rodrigues, Thomas J Mildorf, Ron O Dror, David E Shaw, Michel Bouvier, Els Pardon, Jan Steyaert, Roger K Sunahara, William I Weis, Cheng Zhang, Brian K Kobilka
Salmeterol is a partial agonist for the β2 adrenergic receptor (β2 AR) and the first long-acting β2 AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol's safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β1 AR and β2 AR explain the high receptor-subtype selectivity...
November 2018: Nature Chemical Biology
Tyler E Wagner, Jacob R Becraft, Katie Bodner, Brian Teague, Xin Zhang, Amanda Woo, Ely Porter, Bremy Alburquerque, Brian Dobosh, Oliwia Andries, Niek N Sanders, Jacob Beal, Douglas Densmore, Tasuku Kitada, Ron Weiss
Synthetic mRNA is an attractive vehicle for gene therapies because of its transient nature and improved safety profile over DNA. However, unlike DNA, broadly applicable methods to control expression from mRNA are lacking. Here we describe a platform for small-molecule-based regulation of expression from modified RNA (modRNA) and self-replicating RNA (replicon) delivered to mammalian cells. Specifically, we engineer small-molecule-responsive RNA binding proteins to control expression of proteins from RNA-encoded genetic circuits...
November 2018: Nature Chemical Biology
Martina Wallace, Courtney R Green, Lindsay S Roberts, Yujung Michelle Lee, Justin L McCarville, Joan Sanchez-Gurmaches, Noah Meurs, Jivani M Gengatharan, Justin D Hover, Susan A Phillips, Theodore P Ciaraldi, David A Guertin, Pedro Cabrales, Janelle S Ayres, Daniel K Nomura, Rohit Loomba, Christian M Metallo
Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain...
November 2018: Nature Chemical Biology
Sammy Pontrelli, Riley C B Fricke, Shao Thing Teoh, Walter A Laviña, Sastia Prama Putri, Sorel Fitz-Gibbon, Matthew Chung, Matteo Pellegrini, Eiichiro Fukusaki, James C Liao
Escherichia coli can derive all essential metabolites and cofactors through a highly evolved metabolic system. Damage of pathways may affect cell growth and physiology, but the strategies by which damaged metabolic pathways can be circumvented remain intriguing. Here, we use a ΔpanD (encoding for aspartate 1-decarboxylase) strain of E. coli that is unable to produce the β-alanine required for CoA biosynthesis to demonstrate that metabolic systems can overcome pathway damage by extensively rerouting metabolic pathways and modifying existing enzymes for unnatural functions...
November 2018: Nature Chemical Biology
Sophie Rahuel-Clermont, Michel B Toledano
No abstract text is available yet for this article.
November 2018: Nature Chemical Biology
Yiyun Song
No abstract text is available yet for this article.
November 2018: Nature Chemical Biology
Grant Miura
No abstract text is available yet for this article.
November 2018: Nature Chemical Biology
Mirella Bucci
No abstract text is available yet for this article.
November 2018: Nature Chemical Biology
Caitlin Deane
No abstract text is available yet for this article.
November 2018: Nature Chemical Biology
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