Nature Chemical Biology Contents: February 2017, Volume 13 No 2 pp 127 - 242

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The first issue is now published and is free to view online for a limited time.  Read the first issue TABLE OF CONTENTS February 2017 Volume 13, Issue 2 Obituary Research Highlights News and Views Perspective Brief Communications Articles Advertisement Unexplored opportunities in the druggable human genome This poster presents a categorization of human proteins based on the amount of data on them, highlighting a knowledge deficit and indicating novel drug discovery opportunities.  Download the Poster free online Produced with support from: Illuminating the Druggable Genome Knowledge Management Center  (IDG KMC) Subscribe   Facebook   RSS   Recommend to library   Twitter   Obituary Top Susan Lindquist (1949-2016)   p127 Tricia R Serio doi:10.1038/nchembio.2305 Susan Lindquist passed away on 27 October 2016, far too early for those who marveled at her brilliance through her many contributions to science, for all who knew her directly, and especially for her former trainees. Research Highlights Top RNA modification: Reading Sex-lethal | Biosynthesis: Terrifically tailored peptides | Pancreatic development: Changing identity | RNA structure: Untying Zika's knots News and Views Top Host-pathogen interactions: Nucleotide circles of life and death   pp130 - 131 Lingyin Li doi:10.1038/nchembio.2289 A phosphodiesterase, CdnP, from Mycobacterium tuberculosis (M. tb.) helps the pathogen evade immune detection by degrading the second messenger cyclic di-AMP that alerts the host to its presence. Genetic knockout of CdnP dampens the virulence of the pathogen, suggesting that CdnP inhibitors are potential anti-M. tb. therapeutics. See also: Article by Dey et al. Synthetic biology: Sensing with modular receptors   pp131 - 132 Matthew Brenner, Jang Hwan Cho and Wilson W Wong doi:10.1038/nchembio.2290 Sensing and responding to diverse extracellular signals is a crucial aspect of cellular decision-making that is currently lacking in the synthetic biology toolkit. The development of modular receptor platforms allows for the rewiring of cellular input-output relationships. See also: Article by Schwarz et al. Target engagement: Shining a light   pp133 - 134 Kilian V M Huber doi:10.1038/nchembio.2295 The ability to measure the binding of a compound to its intended target in live cells or tissue is a critical parameter for drug discovery. A new method using polarized light microscopy adds to the current toolbox by enabling monitoring of target engagement in vitro and in vivo at single-cell resolution. See also: Article by Dubach et al. Nitrogenase: A fuel-producing microbe   pp134 - 135 Holger Dobbek doi:10.1038/nchembio.2288 Nitrogenase has the canonical ability to reduce N2 to NH3, but under certain conditions, either in vitro or in vivo, it has the additional capability to convert CO2 to CO and CO to light hydrocarbons. See also: Brief Communication by Rebelein et al. Chemical Biology JOBS of the week Postdoctoral Position Cancer Chemical Biology Oregon Health & Science University (OHSU) School of Medicine More Science jobs from Chemical Biology EVENT Chemical Biology Discussion Group Year-End Symposium 24 May 2017 New York, USA More science events from Perspective Top The pharmacological regulation of cellular mitophagy   pp136 - 146 Nikolaos D Georgakopoulos, Geoff Wells and Michelangelo Campanella doi:10.1038/nchembio.2287 This perspective discusses recent progress in the development of pharmacological tools that initiate mitophagy and spare mitochondrial function and focuses on promising approaches to identify improved reagents. Brief Communications Top Activation and reduction of carbon dioxide by nitrogenase iron proteins   pp147 - 149 Johannes G Rebelein, Martin T Stiebritz, Chi Chung Lee and Yilin Hu doi:10.1038/nchembio.2245 The iron protein components of bacterial nitrogenases are capable of reducing carbon dioxide (CO2) to carbon monoxide (CO) in the absence of their catalytic partners, mimicking the activity of CO dehydrogenase. See also: News and Views by Dobbek A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling   pp150 - 152 Rahul S Kathayat, Pablo D Elvira and Bryan C Dickinson doi:10.1038/nchembio.2262 The development of small-molecule fluorescent probes through addition of a lipidated cysteine residue next to a caged fluorophore enables detection of endogenous cysteine depalmitoylation by acyl-protein thioesterases in vitro and in live cells. Chemical compounds Articles Top Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission   pp153 - 160 Hans Michael Maric, Torben Johann Hausrat, Franziska Neubert, Nils Ole Dalby, Soren Doose et al. doi:10.1038/nchembio.2246 Super-binding peptides based on sequences of glycine receptors that interact with the neuronal scaffold protein gephyrin are useful for isolating and localizing native gephyrin and for modulation of glycinergic synaptic transmission. Genome-wide chemical mapping of O-GlcNAcylated proteins in Drosophila melanogaster   pp161 - 167 Ta-Wei Liu, Mike Myschyshyn, Donald A Sinclair, Samy Cecioni, Kevin Beja et al. doi:10.1038/nchembio.2247 Metabolic labeling of the Drosophila proteome using a chemical ligation approach identifies proteins modified by O-GlcNAc transferase (OGT) including Polycomb proteins at homeotic gene loci and at unexpected sites, implicating OGT in gene-expression regulation. Quantitating drug-target engagement in single cells in vitro and in vivo   pp168 - 173 J Matthew Dubach, Eunha Kim, Katherine Yang, Michael Cuccarese, Randy J Giedt et al. doi:10.1038/nchembio.2248 The use of fluorescence-polarized microscopy, combined with competitive binding with matched fluorescence companion imaging probes, enable target engagement measurements of covalent and reversible small molecule inhibitors in a single cell. Chemical compounds See also: News and Views by Huber A human microprotein that interacts with the mRNA decapping complex   pp174 - 180 Nadia G D'Lima, Jiao Ma, Lauren Winkler, Qian Chu, Ken H Loh et al. doi:10.1038/nchembio.2249 Mass-spectrometry-based proteomics led to the identification of NoBody, a microprotein translated from LINC01420 RNA, which interacts with enhancer of decapping 4 (EDC4) and negatively regulates 5′-to-3′ mRNA decay. Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine   pp181 - 187 Monica Yun Liu, Hedieh Torabifard, Daniel J Crawford, Jamie E DeNizio, Xing-Jun Cao et al. doi:10.1038/nchembio.2250 Saturation mutagenesis, molecular modeling and biochemical analysis revealed that active site interactions involving Thr1372 of TET2 are responsible for controlling its proficiency for stepwise oxidation of 5-methylcytosine residues within DNA. Precise small-molecule recognition of a toxic CUG RNA repeat expansion   pp188 - 193 Suzanne G Rzuczek, Lesley A Colgan, Yoshio Nakai, Michael D Cameron, Denis Furling et al. doi:10.1038/nchembio.2251 Dimeric bis-benzimidazole compounds that bind selectively to toxic expanded r(CUG) RNA repeat sequences were identified and used as a scaffold for covalent modification, site-specific cleavage and on-target assembly of imaging reagents at expanded r(CUG) sequences in cells. Chemical compounds Single-molecule analysis reveals multi-state folding of a guanine riboswitch   pp194 - 201 Vishnu Chandra, Zain Hannan, Huizhong Xu and Maumita Mandal doi:10.1038/nchembio.2252 Single-molecule force spectroscopy and thermodynamics studies reveal six conformational states in the formation of a guanine aptamer, with a 'kissing loop' playing a key role in the conformational switching. Rewiring human cellular input-output using modular extracellular sensors   pp202 - 209 Kelly A Schwarz, Nichole M Daringer, Taylor B Dolberg and Joshua N Leonard doi:10.1038/nchembio.2253 Synthetic biology enables re-engineering of cellular functions by introduction of modular, orthogonal signaling pathways, as illustrated by the reprogramming of human T cells to produce IL-2 in response to vascular endothelial growth factor (VEGF). See also: News and Views by Brenner et al. Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase   pp210 - 217 Ruchi Jain Dey, Bappaditya Dey, Yue Zheng, Laurene S Cheung, Jie Zhou et al. doi:10.1038/nchembio.2254 A mycobacterial phosphodiesterase, CdnP, hydrolyzes bacteria-derived 3′,5′-c-di-AMP as well as host-generated 2′,3′-cGAMP, which activates the host cytosolic surveillance pathway, to dampen host responses. Chemical compounds See also: News and Views by Li Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence   pp218 - 225 Huiqing Zheng, Christopher J Colvin, Benjamin K Johnson, Paul D Kirchhoff, Michael Wilson et al. doi:10.1038/nchembio.2259 A high-throughput screen identifies inhibitors of the M. tuberculosis dormancy regulation system, DosRST, including compounds that inhibit autophosphorylation of the DosS and DosT sensor kinases and those that inhibit the catalytic heme of these kinases. Chemical compounds Molecular insights into the enzyme promiscuity of an aromatic prenyltransferase   pp226 - 234 Ridao Chen, Bingquan Gao, Xiao Liu, Feiying Ruan, Yong Zhang et al. doi:10.1038/nchembio.2263 Structural and functional characterization of an aromatic prenyltransferase reveals a unique spacious hydrophobic pocket with conformational fluctuation and multiple acceptor binding sites that endow it with uncommon enzymatic promiscuity. Chemical compounds Orphan receptor ligand discovery by pickpocketing pharmacological neighbors   pp235 - 242 Tony Ngo, Andrey V Ilatovskiy, Alastair G Stewart, James L J Coleman, Fiona M McRobb et al. doi:10.1038/nchembio.2266 The 'CoINPocket' approach identifies pharmacological similarities between G protein-coupled receptors. On the basis of predicted pharmacological similarity to a few phylogenetically unrelated receptors, the approach identified surrogate ligands for the orphan receptor GPR37L1. 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