Nature Chemical Biology Contents: January 2016, Volume 12 No 1 pp 1 - 50

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TABLE OF CONTENTS January 2016 Volume 12, Issue 1 Research Highlights News and Views Brief Communication Articles Subscribe   Facebook   RSS   Recommend to library   Twitter   Research Highlights Top Antibacterials: Stressing out dormancy | Pharmacological chaperones: A new lens on cataract | Microscopy techniques: A localization module | Cancer therapy: Vitamin C attack News and Views Top Protein Design: Getting to the bottom of the TIM barrel   pp2 - 3 Vikas Nanda doi:10.1038/nchembio.1987 Natural (βα)8-barrel proteins support diverse catalytic functions and are fertile scaffolds for engineering synthetic enzymes. The atomic-resolution structure determination of a computationally guided, de novo-designed symmetric barrel is a long-awaited advance that opens up new opportunities for enzyme design. See also: Article by Huang et al. Probe discovery: Disentangling gene networks   pp3 - 4 Finbarr Hayes doi:10.1038/nchembio.1983 Cell-wall biogenesis in bacteria involves multiple intersecting gene networks. A powerful approach that allies synthetic lethality with small-molecule discovery has now been used to probe these networks and has revealed that the pathway for D-alanylation of teichoic acids in Staphylococcus aureus is a viable target for new antibacterials. See also: Article by Pasquina et al. Transcriptional kinases: Less is more (or less)   pp4 - 5 Thomas G Boyer doi:10.1038/nchembio.1985 Two new studies describe potent and selective inhibitors of CDK8/CDK19. Application of these high-quality probes to several cancer models provides new mechanistic insight and reveals functional dichotomy with respect to Mediator kinases in signal-dependent gene regulation, with important implications for targeted cancer therapy. Chemical Biology JOBS of the week Postdoctoral fellow in synthetic chemistry and chemical biology University of Utah Postdoctoral Associate The Scripps Research Institute (TSRI) Faculty Positions in Translational Plant Sciences University of California, Riverside Faculty Positions in Functional and Chemical Genomics Oklahoma Medical Research Foundation Postdoctoral Position in Stem Cell Engineering Research Nanyang Technological University (NTU) More Science jobs from Chemical Biology EVENT State of the Brain 22-26 May 2016 Alpbach, Austria More science events from Brief Communication Top Structural determinants of reductive terpene cyclization in iridoid biosynthesis   pp6 - 8 Hajo Kries, Lorenzo Caputi, Clare E M Stevenson, Mohammed O Kamileen, Nathaniel H Sherden et al. doi:10.1038/nchembio.1955 The biosynthesis of iridoids, a class of bicyclic monoterpenes, features an atypical cyclization reaction catalyzed by iridoid synthase (ISY). Crystallographic and biochemical characterization of ISY from Catharanthus roseus provides insights into the ISY enzymatic mechanism and highlights similarities with the homologous progesterone 5β-reductase. Articles Top Class D β-lactamases do exist in Gram-positive bacteria   pp9 - 14 Marta Toth, Nuno Tiago Antunes, Nichole K Stewart, Hilary Frase, Monolekha Bhattacharya et al. doi:10.1038/nchembio.1950 Characterization of the first class D β-lactamases in Gram-positive bacteria, including the Bacillaceae family, shows that one, BPU-1, is capable of hydrolyzing a wide variety of β-lactam antibiotics and has a unique substrate-binding mode. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis   pp15 - 21 Courtney R Green, Martina Wallace, Ajit S Divakaruni, Susan A Phillips, Anne N Murphy et al. doi:10.1038/nchembio.1961 Stable-isotope tracing and metabolomics analysis comparing pre-adipocytes and differentiated adipocytes revealed a shift from glucose and glutamine utilization to increased branched chain amino acid catabolic flux to generate acetyl-coenzyme A. CRISPR-Cas9-based target validation for p53-reactivating model compounds   pp22 - 28 Michael Wanzel, Jonas B Vischedyk, Miriam P Gittler, Niklas Gremke, Julia R Seiz et al. doi:10.1038/nchembio.1965 CRISPR-Cas9 based target validation revealed that the sensitivity of the p53-reactivating compound RITA is independent of functional p53 and is reliant on the regulation of the DNA damage-activated Fanconi anemia pathway. De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy   pp29 - 34 Po-Ssu Huang, Kaspar Feldmeier, Fabio Parmeggiani, D Alejandro Fernandez Velasco, Birte Hocker et al. doi:10.1038/nchembio.1966 Despite substantial effort, the de novo design of a stable TIM-barrel protein fold has remained elusive. A Rosetta-based computational strategy identifies a unique 184-residue sequence that adopts a TIM-barrel structure, as revealed by X-ray crystallography. See also: News and Views by Nanda Allosteric regulation of G protein-coupled receptor activity by phospholipids   pp35 - 39 Rosie Dawaliby, Cataldo Trubbia, Cedric Delporte, Matthieu Masureel, Pierre Van Antwerpen et al. doi:10.1038/nchembio.1960 Negatively charged lipids act as allosteric modulators for structural changes and activation of the GPCR β2-adrenergic receptor through direct intracellular interactions between lipid headgroups and the receptor. A synthetic lethal approach for compound and target identification in Staphylococcus aureus   pp40 - 45 Lincoln Pasquina, John P Santa Maria Jr, B McKay Wood, Samir H Moussa, Leigh M Matano et al. doi:10.1038/nchembio.1967 A series of synthetic lethal strategies identifies a small-molecule inhibitor of Staphylococcus aureus DltB, links teichoic acid D-alanylation to virulence and identifies synergistic antibiotic drug combinations. See also: News and Views by Hayes Mechanism of hydrogen activation by [NiFe] hydrogenases   pp46 - 50 Rhiannon M Evans, Emily J Brooke, Sara A M Wehlin, Elena Nomerotskaia, Frank Sargent et al. doi:10.1038/nchembio.1976 [NiFe] hydrogenases contain a conserved arginine (R509) that is suspended over the Ni and Fe atoms. Biochemical, crystallographic and electrochemical analysis of an R509K mutant reveal >100-fold lower oxidation activity despite the maintenance of structural integrity. 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