Nature Chemical Biology Contents: March 2012 Volume 8 Number 3, pp 222 - 318

TABLE OF CONTENTS March 2012 Volume 8, Issue 3 Research Highlights News and Views Brief Communications Articles Corrigenda Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement NPG Asia Materials has re-launched! Now publishing on nature.com, NPG Asia Materials has entered a new phase and is now publishing original research articles in addition to review papers. Read the Editorial and recent content, covering a wide range of topics in materials science. Discover more about NPG Asia Materials: www.nature.com/am   Research Highlights Top Molecular recognition: Sphingomyelin in the groove | Structural biology: Kinase-phosphatase mashup | Antimicrobials: Channel closure | Virology: Cholesterol pass for HCV | Metals: Zinc stores | Domino reactions: Chiral cycloaddition | Rna editing: Following ADAR | Post-Translational modifications: Sulfhydration switch News and Views Top Protein design: A metalloenzyme reloaded pp224 - 225 Birte Hocker doi:10.1038/nchembio.800 Metal ions are frequently used in enzyme catalysis. The extension of computational methods to metalloenzyme redesign opens up new ways to construct enzymes with new functions. Full Text | PDF See also: Article by Khare et al. Alternative DNA structures: G4 DNA in cells: itae missa est? pp225 - 226 Jean-Louis Mergny doi:10.1038/nchembio.793 Application of a synthetic DNA G-quadruplex ligand as a genome-wide probe has provided evidence for G-quadruplex DNA clusters in human cells. Full Text | PDF See also: Article by Rodriguez et al. Protein folding: Chaperoning protein evolution pp226 - 228 Paolo De Los Rios and Pierre Goloubinoff doi:10.1038/nchembio.791 Osmolytes that normally accumulate in cells to equilibrate osmotic stress are also called chemical chaperones because of their ability to stabilize native proteins in vitro. A recent paper shows that various chemical chaperones differently alter the cellular milieu and permit the appearance of osmolyte-specific protein mutant variants during evolution. Full Text | PDF See also: Article by Bandyopadhyay et al. BCR-ABL signaling: A new STATus in CML pp228 - 229 Doriano Fabbro doi:10.1038/nchembio.900 A combination of genetic and pharmacological approaches using mouse leukemia models show that STAT5 phosphorylation is one of the major drivers of the proliferation of Philadelphia chromosome-positive (BCR-ABL-positive or Ph+) chronic myeloid leukemia. Once BCR-ABL expression has been established, JAK2 is required only for lymphoid cell transformation, not for the maintenance of the lymphoid or myeloid leukemia. Full Text | PDF See also: Article by Hantschel et al. Histone deacetylation: IP4 is an epigenetic coregulator pp230 - 231 Tatiana G Kutateladze doi:10.1038/nchembio.795 Inositol tetraphosphate is required for both the incorporation of the histone deacetylase HDAC3 into a repressive complex and its enzymatic activity. Full Text | PDF Chemical Biology JOBS of the week Postdoctoral Fellow Yuh Min Chook, Ph.D., UT Southwestern Scientist / Cell Biology OR Chemical Engineering Kelly Scientific Resources MRes in Chemical Biology of Crop Sustainability & Protection Imperial College London Interdisciplinary MRC PhD Programme Funded by the Medical Resarch Council (MRC) 'Macromolecular machines of biomedical significance' Birkbeck College More Science jobs from Chemical Biology EVENT Therapeutic Applications of Computational Biology and Chemistry (TACBAC) 2012 12-14 March 2012 Cambridge, UK More science events from Brief Communications Top Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin pp232 - 234 Gary J. Patti, Oscar Yanes, Leah P Shriver, Jean-Phillipe Courade, Ralf Tautenhahn, Marianne Manchester and Gary Siuzdak doi:10.1038/nchembio.767 Untargeted metabolomics reveals a dysregulation of sphingolipid production during neuropathic pain exemplified by N,N-dimethylsphingosine, whose upregulation is involved in the generation of pain. First paragraph | Full Text | PDF Using transcriptome sequencing to identify mechanisms of drug action and resistance pp235 - 237 Sarah A Wacker, Benjamin R Houghtaling, Olivier Elemento and Tarun M Kapoor doi:10.1038/nchembio.779 Selection of clones resistant to drugs in human cells, followed by massively parallel transcriptome sequencing of these clones and bioinformatics analyses to identify genes mutated with high frequency, allow for identification of direct targets and indirect resistance mechanisms of cytotoxic drugs. First paragraph | Full Text | PDF Articles Top Chemical chaperones assist intracellular folding to buffer mutational variations pp238 - 245 Anannya Bandyopadhyay, Kanika Saxena, Neha Kasturia, Vijit Dalal, Niraj Bhatt, Asher Rajkumar, Shuvadeep Maity, Shantanu Sengupta and Kausik Chakraborty doi:10.1038/nchembio.768 Osmolytes act as chemical chaperones capable of directly assisting the folding of destabilizing mutations in proteins in vivo, with different osmolytes having distinct targets and thereby increasing the level of genetic variability. Abstract | Full Text | PDF See also: News and Views by De Los Rios & Goloubinoff Evidence for dynamics in proteins as a mechanism for ligand dissociation pp246 - 252 Mary J Carroll, Randall V Mauldin, Anna V Gromova, Scott F Singleton, Edward J Collins and Andrew L Lee doi:10.1038/nchembio.769 NMR and structural analyses of DHFR complexes with inhibitors of differing affinities define a model for ligand dissociation involving conformational switching and a new excited state that mediates the dissociation. Abstract | Full Text | PDF | Chemical compounds Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation pp253 - 261 Jessica E Rexach, Peter M Clark, Daniel E Mason, Rachael L Neve, Eric C Peters and Linda C Hsieh-Wilson doi:10.1038/nchembio.770 Glycosylation is a well-known post-translational modification, but identifying specific roles for the attached glycans is often challenging. The identification and investigation of a new O-GlcNAc site on the transcription factor CREB provides insights into how glycosylation works together with phosphorylation to coordinate neural function. Abstract | Full Text | PDF Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis pp262 - 269 Mary Katherine Tarrant, Hee-Sool Rho, Zhi Xie, Yu Lin Jiang, Christopher Gross, Jeffrey C Culhane, Gai Yan, Jiang Qian, Yoshitaka Ichikawa, Tatsuji Matsuoka, Natasha Zachara, Felicia A Etzkorn, Gerald W Hart, Jun Seop Jeong, Seth Blackshaw, Heng Zhu and Philip A Cole doi:10.1038/nchembio.771 Semisynthetic constructs of protein kinase CK2 incorporating nonhydrolyzable post-translational modifications now demonstrate the interplay between phosphorylation and glycosylation in regulating CK2 stability, controlling substrate specificity and modifying interactions with regulatory proteins. Abstract | Full Text | PDF Spatiotemporal resolution of the Ntla transcriptome in axial mesoderm development pp270 - 276 Ilya A Shestopalov, Cameron L W Pitt and James K Chen doi:10.1038/nchembio.772 The combination of a caged morpholino and a photoactivated fluorophore, allowing isolation of targeted cells by FACS, and subsequent transcriptional profiling reveals new and temporally distinct targets for Ntla during notochord development in zebrafish. Abstract | Full Text | PDF Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia pp277 - 284 Jolanta Grembecka, Shihan He, Aibin Shi, Trupta Purohit, Andrew G Muntean, Roderick J Sorenson, Hollis D Showalter, Marcelo J Murai, Amalia M Belcher, Thomas Hartley, Jay L Hess and Tomasz Cierpicki doi:10.1038/nchembio.773 MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells. Abstract | Full Text | PDF | Chemical compounds BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia pp285 - 293 Oliver Hantschel, Wolfgang Warsch, Eva Eckelhart, Ines Kaupe, Florian Grebien, Kay-Uwe Wagner, Giulio Superti-Furga and Veronika Sexl doi:10.1038/nchembio.775 Although JAK2 inhibitors were proposed to be beneficial in chronic myeloid leukemia, myeloid transformation and STAT5 activation in BCR-ABL–positive leukemias are JAK2 independent. Mechanistic investigations reveal that certain JAK2 inhibitors act via off-target inhibition of BCR-ABL. Abstract | Full Text | PDF See also: News and Views by Fabbro Computational redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis pp294 - 300 Sagar D Khare, Yakov Kipnis, Per Jr Greisen, Ryo Takeuchi, Yacov Ashani, Moshe Goldsmith, Yifan Song, Jasmine L Gallaher, Israel Silman, Haim Leader, Joel L Sussman, Barry L Stoddard, Dan S Tawfik and David Baker doi:10.1038/nchembio.777 Metals serve as unique structural and functional elements in biology, providing a wealth of reactivities not available in a wholly proteinogenic active site. The computational redesign and directed evolution of zinc enzymes to create a phosphotriesterase provides insights into how these elements can be utilized in the development of new functions. Abstract | Full Text | PDF See also: News and Views by Hocker Small-molecule–induced DNA damage identifies alternative DNA structures in human genes pp301 - 310 Raphaël Rodriguez, Kyle M Miller, Josep V Forment, Charles R Bradshaw, Mehran Nikan, Sébastien Britton, Tobias Oelschlaegel, Blerta Xhemalce, Shankar Balasubramanian and Stephen P Jackson doi:10.1038/nchembio.780 Identifying DNA sequences that adopt alternative structures within the context of genomic DNA presents a major challenge. Pyridostatin, a G-quadruplex–specific chemical probe, was shown to induce DNA damage at specific genomic sites, including the proto-oncogene SRC, leading to cell cycle arrest in human cancer cells. Abstract | Full Text | PDF | Chemical compounds See also: News and Views by Mergny Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase pp311 - 317 Tracy L Keller, Davide Zocco, Mark S Sundrud, Margaret Hendrick, Maja Edenius, Jinah Yum, Yeon-Jin Kim, Hak-Kyo Lee, Joseph F Cortese, Dyann F Wirth, John David Dignam, Anjana Rao, Chang-Yeol Yeo, Ralph Mazitschek and Malcolm Whitman doi:10.1038/nchembio.790 Halofuginone was recently shown to inhibit the differentiation of T helper 17 (TH17) cells, which are associated with autoimmune diseases. The demonstration that halofuginone inhibits prolyl-tRNA synthetase activity explains the observed activation of the amino acid response pathway in TH17 cells and identifies amino acid restriction pathways as potential drug targets in inflammatory disease. Abstract | Full Text | PDF | Chemical compounds Corrigenda Top Identifying polyglutamine protein species in situ that best predict neurodegeneration p318 Jason Miller, Montserrat Arrasate, Elizabeth Brooks, Clare Peters Libeu, Justin Legleiter, Danny Hatters, Jessica Curtis, Kenneth Cheung, Preethi Krishnan, Siddhartha Mitra, Kartika Widjaja, Benjamin A Shaby, Gregor P Lotz, Yvonne Newhouse, Emily J Mitchell, Alex Osmand, Michelle Gray, Vanitha Thulasiramin, Frederic Saudou, Mark Segal, X William Yang, Eliezer Masliah, Leslie M Thompson, Paul J Muchowski, Karl H Weisgraber and Steven Finkbeiner doi:10.1038/nchembio0312-318a Full Text | PDF Dafadine inhibits DAF-9 to promote dauer formation and longevity of Caenorhabditis elegans  p318 Genna M Luciani, Lilia Magomedova, Rachel Puckrin, Malene L Urbanus, Iain M Wallace, Guri Giaever, Corey Nislow, Carolyn L Cummins and Peter J Roy doi:10.1038/nchembio0312-318b Full Text | PDF Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors p318 Alexander Adibekian, Brent R Martin, Chu Wang, Ku-Lung Hsu, Daniel A Bachovchin, Sherry Niessen, Heather Hoover and Benjamin F Cravatt doi:10.1038/nchembio0312-318c Full Text | PDF Top Advertisement Scientific American monthly table of contents e-alerts Sign up today! 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