Nature Chemical Biology Contents: July 2016, Volume 12 No 7 pp 467 - 573

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TABLE OF CONTENTS July 2016 Volume 12, Issue 7 Research Highlights News and Views Review Brief Communication Articles Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Launching in January 2017 - Nature Biomedical Engineering Discovery and technology for human health A new online journal for bench scientists, clinicians and medical engineers. Register for the journal's e-alert to receive content and news from the beginning.   Research Highlights Top Antibiotic discovery: Macrolides en masse | RNA structure: PARISian arches | Methanogenesis: A radical approach | Ion channels: Calcium channels work together News and Views Top Drug discovery: Zebrafish uncover novel antipsychotics   pp468 - 469 Louis C Leung and Philippe Mourrain doi:10.1038/nchembio.2114 Two independent high-throughput zebrafish behavioral screens of tens of thousands of compounds identify the 'finazines', a novel group of antipsychotics, and their endogenous genetic target, the [sigma]1 receptor. See also: Article by Rennekamp et al. | Article by Bruni et al. Chromatin targeting: A BET inhibitor workaround   pp469 - 470 Christopher J Burns doi:10.1038/nchembio.2107 A phenotypic cell-based screen identifies an inhibitor of BET bromodomain transcriptional activity via inhibition of the alternative bromodomain-containing protein TAF1. See also: Article by Sdelci et al. Chemical genetics: Unraveling cell death mysteries   pp470 - 471 Xiomaris M Cotto-Rios and Evripidis Gavathiotis doi:10.1038/nchembio.2110 Non-apoptotic regulated cell death is not fully characterized, particularly for ferroptosis, the iron- and ROS-dependent form of regulated cell death. A systematic approach using modulatory profiling and cell line sensitivity analysis has unraveled the association of lipid metabolism with ferroptosis and enabled the discovery of a novel specific ferroptosis inducer. See also: Article by Shimada et al. Chemical Biology JOBS of the week Postdoctoral Fellow MSKCC More Science jobs from Chemical Biology EVENT 12th Annual Tri-Institutional Chemical Biology Symposium 17 August 2016 New York, USA More science events from Review Top Progress and prospects for small-molecule probes of bacterial imaging   pp472 - 478 Ozden Kocaoglu and Erin E Carlson doi:10.1038/nchembio.2109 Biomolecule-specific small-molecule probes, in contrast to genetically encoded tags, can visualize peptidoglycan, lipids, nucleic acids and glycans and have proven useful for imaging of the unique subcellular compartments and environment of bacteria. Brief Communication Top Prdm4 induction by the small molecule butein promotes white adipose tissue browning   pp479 - 481 No-Joon Song, Seri Choi, Prashant Rajbhandari, Seo-Hyuk Chang, Suji Kim et al. doi:10.1038/nchembio.2081 Microarray analysis of butein-treated adipocytes results in the identification of the PR domain containing 4 (Prdm4) transcription factor, which stimulates WAT browning and lipolysis and protects against diet-induced obesity. Chemical compounds Advertisement Nature Collection: Computational Biology Advances in technology across all areas of science have ushered in an era of big data, providing researchers with unprecedented opportunities to understand how biological systems function and interact. Access this collection free online for six months Produced with support from: IBM Research & IBM Watson Health   Articles Top Metabolite concentrations, fluxes and free energies imply efficient enzyme usage   pp482 - 489 Junyoung O Park, Sara A Rubin, Yi-Fan Xu, Daniel Amador-Noguez, Jing Fan et al. doi:10.1038/nchembio.2077 Metabolic tracer and free energy analysis of metabolic fluxes and pool sizes in E. coli, yeast and a mammalian cell line reveals a conservation of absolute metabolite concentrations that is constrained by thermodynamics and efficient enzyme utilization. An intrinsically disordered entropic switch determines allostery in Phd-Doc regulation   pp490 - 496 Abel Garcia-Pino, Steven De Gieter, Ariel Talavera, Henri De Greve, Rouslan G Efremov et al. doi:10.1038/nchembio.2078 Crystal structure analysis of the Phd transcription factor bound to the DNA operator combined with biophysical studies reveal an interplay between intrinsically disordered regions and conditional cooperativity for operon binding and repression. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis   pp497 - 503 Kenichi Shimada, Rachid Skouta, Anna Kaplan, Wan Seok Yang, Miki Hayano et al. doi:10.1038/nchembio.2079 Modulatory profiling of lethal small-molecule compounds identified FIN56 as an inducer of ferroptosis. FIN56 promotes the degradation of glutathione peroxidase 4 and directly activates squalene synthase, an enzyme involved in cholesterol synthesis. Chemical compounds See also: News and Views by Cotto-Rios & Gavathiotis Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk   pp504 - 510 Sara Sdelci, Charles-Hugues Lardeau, Cynthia Tallant, Freya Klepsch, Bjorn Klaiber et al. doi:10.1038/nchembio.2080 Chemical screening using a newly developed fluorescence-based assay for chromatin reactivation led to the identification of small-molecule inhibitors of the second bromodomain of TAF1 that synergize with BRD4 inhibitors. Chemical compounds See also: News and Views by Burns The antitumor toxin CD437 is a direct inhibitor of DNA polymerase α   pp511 - 515 Ting Han, Maria Goralski, Emanuela Capota, Shae B Padrick, Jiwoong Kim et al. doi:10.1038/nchembio.2082 A forward-genetic screen revealed that the mutations in DNA polymerase α (POLA1) are resistant to the effects of CD437. The direct interaction of CD437 and POLA1 blocks DNA replication and promotes cancer cell death. Membrane anchoring stabilizes and favors secretion of New Delhi metallo-[beta]-lactamase   pp516 - 522 Lisandro J Gonzalez, Guillermo Bahr, Toshiki G Nakashige, Elizabeth M Nolan, Robert A Bonomo et al. doi:10.1038/nchembio.2083 Membrane anchoring protects metallo-[beta]-lactamase NDM-1 from degradation while favoring its secretion into outer-membrane vesicles. This provides carbapenem resistance to bacteria that are sensitive to zinc starvation, which causes degradation of these enzymes. A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes   pp523 - 530 Monique P C Mulder, Katharina Witting, Ilana Berlin, Jonathan N Pruneda, Kuen-Phon Wu et al. doi:10.1038/nchembio.2084 A ubiquitin analog used as an activity-based probe of ubiquitin conjugation enzymes, E1, E2 and E3 covalently traps these enzymes without transfer to substrates. The probes can be used in structural and functional studies and to visualize enzyme activity in cells. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells   pp531 - 538 Maia Vinogradova, Victor S Gehling, Amy Gustafson, Shilpi Arora, Charles A Tindell et al. doi:10.1038/nchembio.2085 KDM5 histone demethylases promote the survival of drug-tolerant persister (DTP) cells in certain cancers. CPI-455, a chemical probe specific for KDM5, elevates cellular H3K4 methylation levels and reduces DTP cell numbers, suggesting that KDM5 is a viable target for cancer combination treatment. Chemical compounds See also: Article by Johansson et al. Structural analysis of human KDM5B guides histone demethylase inhibitor development   pp539 - 545 Catrine Johansson, Srikannathasan Velupillai, Anthony Tumber, Aleksandra Szykowska, Edward S Hookway et al. doi:10.1038/nchembio.2087 X-ray crystallographic analyses of KDM5B provide a view of the enzyme's iron(II)- and 2-oxoglutarate-containing catalytic core, and structures of KDM5B complexes with small-molecule inhibitors reveal selectivity profiles for multiple compound chemotypes. Chemical compounds See also: Article by Vinogradova et al. NSUN3 methylase initiates 5-formylcytidine biogenesis in human mitochondrial tRNAMet   pp546 - 551 Saori Nakano, Takeo Suzuki, Layla Kawarada, Hiroyoshi Iwata, Kana Asano et al. doi:10.1038/nchembio.2099 Human mitochondrial tRNAMet has a 5-formylcytidine (f5C) modification at the first anticodon position that is required for correct decoding of the AUA codon as methionine. The first step in the biosynthesis of f5C involves the S-adenosylmethionine-dependent methylation of cytidine 34 by the NSUN3 methyltransferase. σ1 receptor ligands control a switch between passive and active threat responses   pp552 - 558 Andrew J Rennekamp, Xi-Ping Huang, You Wang, Samir Patel, Paul J Lorello et al. doi:10.1038/nchembio.2089 Small molecules identified in two high-throughput screens modulate a strobe-light-induced fear response in zebrafish larvae described as 'innate freezing'. Some compounds cause escape-like behavior, including several that target the sigma-1 (σ1) receptor. See also: News and Views by Leung & Mourrain Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds   pp559 - 566 Giancarlo Bruni, Andrew J Rennekamp, Andrea Velenich, Matthew McCarroll, Leo Gendelev et al. doi:10.1038/nchembio.2097 A screening approach involving ten larval zebrafish behavior assays and the similarity search tool, phenoBlast, for compounds that phenocopy the antipsychotic haloperidol identifies finazines that may work partially through the sigma-1 ([sigma]1) receptor. See also: News and Views by Leung & Mourrain Mitochondrial DNA repair and replication proteins revealed by targeted chemical probes   pp567 - 573 Simon Wisnovsky, Sae Rin Jean and Shana O Kelley doi:10.1038/nchembio.2102 An siRNA screen of cells treated with a mitochondrial-targeted DNA oxidizing agent identifies proteins such as RAD23A, XRCC4, and POL[theta] that mediate mitochondrial DNA repair and replication. 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