Nature Chemical Biology Contents: February 2012 Volume 8 Number 2, pp 134 - 220

TABLE OF CONTENTS February 2012 Volume 8, Issue 2 Poster Research Highlights News and Views Brief Communications Articles Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Nature Chemical Biology Free Poster on Human protein methyltransferases Nature Chemical Biology presents a poster highlighting the human protein methyltransferase families, the small molecules known to target them and the prospects for PMT-focused drug development. Download the Poster today by visiting: www.nature.com/nchembio/poster/hpm Poster sponsored by:   Poster Top Human protein methyltransferases The poster "The human protein methyltransferases," which highlights the families of protein methyltransferases (PMTs) and explores prospects for PMT-focused drug development, accompanies this issue. The poster was produced with support from Epizyme. Research Highlights Top Protein-protein interactions: In the TANK | Enzyme engineering: Just a jump to the left | Methods: Zebrafish click | Allostery: A systematic search | Metabolism: Closing the loop | Translation: Ribosome 3.0 | Molecular switches: The pore of the matter | Chemical genetics: Bumping into AMPK substrates News and Views Top Ion channels: Cooperativity in twin gatings pp136 - 137 Lei Zhou doi:10.1038/nchembio.776 Patch-clamp fluorometry measurements of cAMP binding and channel opening combined with global kinetic fitting revealed that ligand binding to the tetrameric hyperpolarization-activated cyclic nucleotide-gated channel is favored at the second and fourth binding events. Full Text | PDF See also: Article by Kusch et al. Glycobiology: Enzyme deficiencies deciphered pp137 - 138 Lena Kjellen doi:10.1038/nchembio.778 Mucopolysaccharidoses are inherited disorders in which inactivation of lysosomal enzymes results in accumulation of glycosaminoglycans within cells, causing tissue and organ dysfunction. A method to determine the unique end structures of the accumulated glycosaminoglycans offers a new way for diagnosis. Full Text | PDF See also: Article by Lawrence et al. Signaling: An oxysterol ligand for Smoothened pp139 - 140 Hayley J Sharpe and Frederic J de Sauvage doi:10.1038/nchembio.774 20(S)-hydroxycholesterol, a naturally occurring oxysterol, activates the Hedgehog signaling pathway by directly binding an allosteric site on Smoothened. Full Text | PDF See also: Article by Nachtergaele et al. Chemical Biology JOBS of the week Fourteen Research Positions (13 PhD Students + 1 Postdoc) in bio-diagnosis and chemical structure elucidation EDA-EMERGE 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 Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor pp141 - 143 Solveigh C Koeberle, Johannes Romir, Stefan Fischer, Andreas Koeberle, Verena Schattel, Wolfgang Albrecht, Christian Grütter, Oliver Werz, Daniel Rauh, Thilo Stehle and Stefan A Laufer doi:10.1038/nchembio.761 Studies elucidating the role of p38α MAPK in diverse biological processes are limited by the lack of a specific inhibitor. Skepinone-L is a highly selective ATP-competitive inhibitor of p38 with excellent potency in vivo. First paragraph | Full Text | PDF | Chemical compounds Chemical informatics and target identification in a zebrafish phenotypic screen pp144 - 146 Christian Laggner, David Kokel, Vincent Setola, Alexandra Tolia, Henry Lin, John J Irwin, Michael J Keiser, Chung Yan J Cheung, Daniel L Minor Jr, Bryan L Roth, Randall T Peterson and Brian K Shoichet doi:10.1038/nchembio.732 A cheminformatics approach helps identify proteins such as GPCRs, ion channels and kinases that are targeted by small molecules that give phenotypes in a zebrafish behavioral assay. First paragraph | Full Text | PDF | Chemical compounds Articles Top Knot formation in newly translated proteins is spontaneous and accelerated by chaperonins pp147 - 153 Anna L Mallam and Sophie E Jackson doi:10.1038/nchembio.742 Threading of a polypeptide chain is required for knotted proteins to adopt active conformations. A cell-free translation system in conjunction with pulse proteolysis to track folding of trefoil knotted proteins reveal that these knots form spontaneously, but GroEL–GroES enhances the rate of post-translational knot formation. Abstract | Full Text | PDF A ketosynthase homolog uses malonyl units to form esters in cervimycin biosynthesis pp154 - 161 Tom Bretschneider, Georg Zocher, Michelle Unger, Kirstin Scherlach, Thilo Stehle and Christian Hertweck doi:10.1038/nchembio.746 Polyketide synthases make use of a limited set of enzymes to create diverse natural products. The discovery that a ketosynthase homolog catalyzes ester bond formation instead of the typical Claisen condensation uncovers a previously unknown mechanism to generate chemical diversity. Abstract | Full Text | PDF | Chemical compounds How subunits cooperate in cAMP-induced activation of homotetrameric HCN2 channels pp162 - 169 Jana Kusch, Susanne Thon, Eckhard Schulz, Christoph Biskup, Vasilica Nache, Thomas Zimmer, Reinhard Seifert, Frank Schwede and Klaus Benndorf doi:10.1038/nchembio.747 The four subunits of the tetrameric voltage-sensitive HCN channel have different cAMP binding affinities, with the second and fourth binding events being positively cooperative and the third being negatively cooperative, suggesting a double-dimeric organization of the channel. Abstract | Full Text | PDF See also: News and Views by Zhou Primary amines protect against retinal degeneration in mouse models of retinopathies pp170 - 178 Akiko Maeda, Marcin Golczak, Yu Chen, Kiichiro Okano, Hideo Kohno, Satomi Shiose, Kaede Ishikawa, William Harte, Grazyna Palczewska, Tadao Maeda and Krzysztof Palczewski doi:10.1038/nchembio.759 Compounds containing a primary amino group can protect against light-induced retinal degeneration in a mouse model of Stargardt’s disease and age-related retinal degeneration by forming a transient Schiff base with all-trans-retinal, lowering its intracellular concentration and preventing accumulation of lipofuscin chromophores in the eye. Abstract | Full Text | PDF Natural product–inspired cascade synthesis yields modulators of centrosome integrity pp179 - 184 Heiko Dückert, Verena Pries, Vivek Khedkar, Sascha Menninger, Hanna Bruss, Alexander W Bird, Zoltan Maliga, Andreas Brockmeyer, Petra Janning, Anthony Hyman, Stefan Grimme, Markus Schürmann, Hans Preut, Katja Hübel, Slava Ziegler, Kamal Kumar and Herbert Waldmann doi:10.1038/nchembio.758 Natural product–inspired compounds are primed to interact with and manipulate biological processes, but obtaining these complex molecules poses synthetic challenges. The development of a 12-step, 1-pot cascade reaction leads to the 'centrocountins', tetrahydroindoloquinolizines that modulate mitosis by targeting the centrosome-associated proteins nucleophosmin and Crm1. Abstract | Full Text | PDF | Chemical compounds Small-molecule proteostasis regulators for protein conformational diseases pp185 - 196 Barbara Calamini, Maria Catarina Silva, Franck Madoux, Darren M Hutt, Shilpi Khanna, Monica A Chalfant, S Adrian Saldanha, Peter Hodder, Bradley D Tait, Dan Garza, William E Balch and Richard I Morimoto doi:10.1038/nchembio.763 Screens of large compound libraries identify new small–molecule proteostasis regulators that, by enhancing the activity of the heat shock response factor HSF–1 and by activating other components of the proteostasis network, such as the antioxidant response or the unfolded protein response pathways, restore protein folding in multiple models of protein conformational diseases. Abstract | Full Text | PDF Disease-specific non–reducing end carbohydrate biomarkers for mucopolysaccharidoses pp197 - 204 Roger Lawrence, Jillian R Brown, Kanar Al-Mafraji, William C Lamanna, James R Beitel, Geert-Jan Boons, Jeffrey D Esko and Brett E Crawford doi:10.1038/nchembio.766 Mucopolysaccharidoses are caused by a deficiency in GAG processing and can often be treated if the dysfunctional enzyme can be identified. A chemical derivatization strategy in combination with biochemical logic now yields a series of biomarkers that can be used to distinguish these disorders. Abstract | Full Text | PDF | Chemical compounds See also: News and Views by Kjellen Timing facilitated site transfer of an enzyme on DNA pp205 - 210 Joseph D Schonhoft and James T Stivers doi:10.1038/nchembio.764 DNA repair proteins require efficient pathways to search for DNA damage lesions within a large genome. Kinetic trapping experiments define the rates of human uracil DNA glycosylase hopping and sliding along damaged DNA substrates and highlight the role of the phosphodiester backbone in DNA sliding. Abstract | Full Text | PDF Oxysterols are allosteric activators of the oncoprotein Smoothened  pp211 - 220 Sigrid Nachtergaele, Laurel K Mydock, Kathiresan Krishnan, Jayan Rammohan, Paul H Schlesinger, Douglas F Covey and Rajat Rohatgi doi:10.1038/nchembio.765 20(S)-hydroxycholesterol binds to Smo at a site distinct from cyclopamine and activates signaling via an allosteric mechanism. A new alkyne oxysterol analog selectively captures Smo from membrane extracts and provides a new method for detecting protein-sterol interactions. Abstract | Full Text | PDF | Chemical compounds See also: News and Views by Sharpe & de Sauvage Top Advertisement Subscribe today to Nature Chemical Biology Reflecting the diversity and excitement of chemical biology research. 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