Nature Chemical Biology Contents: April 2017, Volume 13 No 4 pp 339 - 450

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TABLE OF CONTENTS April 2017 Volume 13, Issue 4 Commentary Research Highlights News and Views Review Brief Communications Articles Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Nature Reviews Microbiology: Collection on Antimicrobial Resistance  This collection of articles from several Nature journals describes how antimicrobial resistance emerges and details discovery strategies for urgently needed new antimicrobials.  Access this collection free online for six months Produced with support from  Merck & Co., Inc., Kenilworth, NJ, USA   Advertisement nature.com webcasts Join us for our upcoming webcast followed by live Q&A: NEW INNOVATIONS IN DRUG DELIVERY TECHNOLOGY  Presented by BioPharma Dealmakers Date: Wednesday, March 29, 2017 Time: 8AM PDT | 11AM EDT | 4PM BST | 5PM CEST REGISTER FOR FREE Sponsored by: Corium International | Portal Instruments Inc. | TissueGen Inc. | TrioxNano     Commentary Top Simultaneous quantification of protein order and disorder   pp339 - 342 Pietro Sormanni, Damiano Piovesan, Gabriella T Heller, Massimiliano Bonomi, Predrag Kukic et al. doi:10.1038/nchembio.2331 Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them. Research Highlights Top Development: Marking the transition | Bioconjugation: Methionine's time to shine | Drug discovery: Uncoupling coupled transport | Imaging: Luciferase matchmaker News and Views Top Fatty acid synthases: Re-engineering biofactories   pp344 - 345 Timm Maier doi:10.1038/nchembio.2338 Systematically modifying biological assembly lines for the synthesis of novel products remains a challenge. Structural insights and computational modeling have now paved the way for efficient redesigns of giant fatty acid synthases. See also: Brief Communication by Zhu et al. | Brief Communication by Gajewski et al. Chromatin biology: Breaking into the PRC2 cage   pp345 - 346 Daniel Holoch and Raphael Margueron doi:10.1038/nchembio.2313 New small-molecule inhibitors of the histone methyltransferase PRC2 interfere with the allosteric activation of enzymatic activity. These compounds are effective against PRC2-dependent tumors that are resistant to catalytic inhibitors and provide important new tools for altering chromatin regulation. See also: Article by Qi et al. | Article by He et al. Protein folding: Illuminating chaperone activity   pp346 - 347 Danny M Hatters doi:10.1038/nchembio.2332 Pharmacological chaperones are small drugs that stabilize a protein's fold and are being developed to treat diseases arising from protein misfolding. A mathematical framework to model their activity in cells enables insight into their mechanism and capacity to rescue protein foldedness. See also: Brief Communication by Hingorani et al. Signaling: Spatial regulation of axonal cAMP   pp348 - 349 Pierre Vincent and Liliana R Castro doi:10.1038/nchembio.2339 In early-stage developing neurons, the cAMP-PKA (protein kinase A) signaling pathway is strongly inhibited. This negative control is later removed, unleashing cAMP-PKA signaling, particularly in distal axonal parts, thus allowing for axonal growth. See also: Article by Gorshkov et al. Chemical Biology JOBS of the week Lecturer in Chemical Biology (3 Posts Available) University of Leicester Postdoctoral Scientist, Chemical Biology Johnson & Johnson Postdoctoral position in Chemical and Structural Biology of RNA The Scripps Research Institute PostDoc Investigating Ladderane Lipid Biosynthesis Max Planck Institute for Medical Research Postdoctoral Fellow Vancouver Prostate Centre More Science jobs from Chemical Biology EVENT EFMC-ASMC'17 - EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry 27 - 31 August 2017 Vienna, Austria More science events from Review Top Versatile modes of cellular regulation via cyclic dinucleotides   pp350 - 359 Petya Violinova Krasteva and Holger Sondermann doi:10.1038/nchembio.2337 A review of the roles of cyclic dinucleotides (CDNs) in signaling systems including transcription, ion transport, bacterial secretion and eukaryotic immune responses, highlighting the diverse binding modes of CDNs by target proteins and functional insights gained from structural studies. Brief Communications Top Expanding the product portfolio of fungal type I fatty acid synthases   pp360 - 362 Zhiwei Zhu, Yongjin J Zhou, Anastasia Krivoruchko, Martin Grininger, Zongbao K Zhao et al. doi:10.1038/nchembio.2301 Integration of heterologous enzymes into the reaction chambers of fungal fatty acid synthases (FASs) demonstrates the capacity of these megaenzymes for engineered production of short- and medium-chain fatty acids and methyl ketones. See also: Brief Communication by Gajewski et al. | News and Views by Maier Engineering fatty acid synthases for directed polyketide production   pp363 - 365 Jan Gajewski, Floris Buelens, Sascha Serdjukow, Melanie Janszen, Nina Cortina et al. doi:10.1038/nchembio.2314 In vitro and in silico analysis enables the rational design of fatty acid synthase (FAS)-mediated pathways for the compartmentalized production of desirable fatty acids and a polyketide lactone. See also: Brief Communication by Zhu et al. | News and Views by Maier Structure and specificity of a permissive bacterial C-prenyltransferase   pp366 - 368 Sherif I Elshahawi, Hongnan Cao, Khaled A Shaaban, Larissa V Ponomareva, Thangaiah Subramanian et al. doi:10.1038/nchembio.2285 Discovery and characterization of an unusually permissive C-prenyltransferase provides a biocatalytic route for generating novel prenylated compounds, including daptomycin derivatives with increased potency. Chemical compounds Ligand-promoted protein folding by biased kinetic partitioning   pp369 - 371 Karan S Hingorani, Matthew C Metcalf, Derrick T Deming, Scott C Garman, Evan T Powers et al. doi:10.1038/nchembio.2303 Pharmacological chaperones improve folding of destabilized Escherichia coli dihydrofolate reductase (DHFR) and human disease-linked α-galactosidase A (α-GAL) by biasing the kinetic partitioning between folding, aggregation, and degradation. Chaperoning spares DHFR from aggregation and α-GAL from degradation. See also: News and Views by Hatters Advertisement Looking to recruit? Limited time offer from Naturejobs:  Get a 20% discount on our Premium job posting package when you buy before March 31, 2017. Reach a potential audience of 10.8 million users* via nature.com Be seen first by candidates — your position will appear at the top of related searches for 60 days and be displayed prominently on the Naturejobs home page as Job of the Week. Plus appear as 'Featured' in search results Post a job now. * Publisher data 2016     Articles Top HTS-compatible FRET-based conformational sensors clarify membrane receptor activation   pp372 - 380 Pauline Scholler, David Moreno-Delgado, Nathalie Lecat-Guillet, Etienne Doumazane, Carine Monnier et al. doi:10.1038/nchembio.2286 Optimizing the signal-to-noise ratio in time-resolved FRET through generation of agonist-responsive cell-surface receptor biosensors, including GABAB receptors and EGFR, which are useful for monitoring conformational changes associated with receptor activation. Chemical compounds An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED   pp381 - 388 Wei Qi, Kehao Zhao, Justin Gu, Ying Huang, Youzhen Wang et al. doi:10.1038/nchembio.2304 H3K27me3 binding to the EED pocket of the Polycomb repressive complex 2 (PRC2) is required to activate PRC2. An allosteric small-molecule inhibitor of PRC2 was identified that binds to the EED pocket and blocks PRC2 methyltransferase activity in cells. Chemical compounds See also: Article by He et al. | News and Views by Holoch & Margueron The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex   pp389 - 395 Yupeng He, Sujatha Selvaraju, Michael L Curtin, Clarissa G Jakob, Haizhong Zhu et al. doi:10.1038/nchembio.2306 A pyrrolidine-based small-molecule inhibitor competes with H3K27me3 for binding to EED leading to inactivation of PRC2 and global reduction in H3K27me3 levels. Chemical compounds See also: Article by Qi et al. | News and Views by Holoch & Margueron In vitro reconstitution demonstrates the cell wall ligase activity of LCP proteins   pp396 - 401 Kaitlin Schaefer, Leigh M Matano, Yuan Qiao, Daniel Kahne and Suzanne Walker doi:10.1038/nchembio.2302 Reconstitution experiments using substrates prepared by chemoenzymatic synthesis demonstrate that three LCP family proteins catalyze the ligation of wall teichoic acids to peptidoglycan in the biosynthesis of the Staphylococcus aureus cell wall. A water-mediated allosteric network governs activation of Aurora kinase A   pp402 - 408 Soreen Cyphers, Emily F Ruff, Julie M Behr, John D Chodera and Nicholas M Levinson doi:10.1038/nchembio.2296 Spectroscopic studies of allosteric activation of Aurora A kinase using a site-specific infrared probe combined with FRET analysis and molecular dynamics simulations reveals a water-mediated hydrogen bond network in the active site that regulates Aurora A activity. A tight tunable range for Ni(II) sensing and buffering in cells   pp409 - 414 Andrew W Foster, Rafael Pernil, Carl J Patterson, Andrew J P Scott, Lars-Olof Palsson et al. doi:10.1038/nchembio.2310 The Ni(ii) affinity of Ni(ii) sensor InrS is attuned to buffered Ni(ii) concentrations, explaining why these two parameters co-vary for different metals over many orders of magnitude. Selective in vivo metabolic cell-labeling-mediated cancer targeting   pp415 - 424 Hua Wang, Ruibo Wang, Kaimin Cai, Hua He, Yang Liu et al. doi:10.1038/nchembio.2297 Metabolic labeling of the cell surface with a caged azide sugar enabled cleavage-mediated activation by enzymes overexpressed in cancer cells, allowing enhanced targeted delivery of a doxorubicin conjugate through copper-free click chemistry. Chemical compounds AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons   pp425 - 431 Kirill Gorshkov, Sohum Mehta, Santosh Ramamurthy, Gabriele V Ronnett, Feng-Quan Zhou et al. doi:10.1038/nchembio.2298 A gradient of cAMP in developing hippocampal neurons that is important for axon elongation is shaped by spatial differences in phosphodiesterase localization and is maintained by AKAP-anchored PKA, as revealed by using FRET-based biosensors. See also: News and Views by Vincent & Castro Evolution of a split RNA polymerase as a versatile biosensor platform   pp432 - 438 Jinyue Pu, Julia Zinkus-Boltz and Bryan C Dickinson doi:10.1038/nchembio.2299 Design of a proximity-dependent split RNA polymerase system and its optimization by phage-assisted continuous evolution (PACE) enabled the development of a family of activity-dependent split RNA polymerase biosensors regulated by small molecules or light. The GlcN6P cofactor plays multiple catalytic roles in the glmS ribozyme   pp439 - 445 Jamie L Bingaman, Sixue Zhang, David R Stevens, Neela H Yennawar, Sharon Hammes-Schiffer et al. doi:10.1038/nchembio.2300 Experimental work and computational modeling together reveal a suite of catalytic roles of the GlcN6P cofactor in the glmS ribozyme, including activation of the nucleophile, electrostatic stabilization, and alignment of the active site. An orthogonalized platform for genetic code expansion in both bacteria and eukaryotes   pp446 - 450 James S Italia, Partha Sarathi Addy, Chester J J Wrobel, Lisa A Crawford, Marc J Lajoie et al. doi:10.1038/nchembio.2312 In Escherichia coli, replacement of the endogenous tryptophanyl-tRNA synthetase-tRNA pair with its counterpart from Saccharomyces cerevisiae liberates the bacterial counterpart for directed evolution to incorporate unnatural amino acids in both E. coli and eukaryotes. 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