ChemBioChem

Cover image for Vol. 9 Issue 11

July 21, 2008

Volume 9, Issue 11

Pages 1677–1850

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Highlight
    7. Communications
    8. Full Papers
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    1. Cover Picture: An Indole-Binding Site is a Major Determinant of the Ligand Specificity of the GABA Type A Receptor-Associated Protein GABARAP (ChemBioChem 11/2008) (page 1677)

      Yvonne Thielmann, Jeannine Mohrlüder, Bernd W. Koenig, Thomas Stangler, Rudolf Hartmann, Karin Becker, Hans-Dieter Höltje and Dieter Willbold

      Article first published online: 11 JUL 2008 | DOI: 10.1002/cbic.200890040

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      The cover picture shows the NMR structure of the GABAA receptor associated protein (GABARAP) in a ribbon and surface representation with two bound tryptophans located in hydrophobic pockets on the surface of GABARAP. NMR spectroscopy allowed the mapping of the indole binding sites onto the surface of the protein and provided a quantitative estimate of the binding affinity. A subset of amide 1H–15N correlation peaks of GABARAP in the two-dimensional NMR spectrum show gradual positional shifts upon titration with tryptophan and other indole derivatives. This behavior is indicative of rapid ligand exchange on and off the binding site. Biological relevance of the indole binding sites for various GABARAP ligand interactions is indicated by the presence of conserved tryptophan residues in GABARAP ligands. Further details can be found in the article by D. Willbold, B. W. Koenig et al. on p. 1767 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Highlight
    7. Communications
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    1. Graphical Abstract: ChemBioChem 11/2008 (pages 1679–1686)

      Article first published online: 11 JUL 2008 | DOI: 10.1002/cbic.200890041

  3. News

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    3. Graphical Abstract
    4. News
    5. Review
    6. Highlight
    7. Communications
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  4. Review

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    3. Graphical Abstract
    4. News
    5. Review
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    1. Embryonic Stem Cells: The Mouse Source—Vehicle for Mammalian Genetics and Beyond (Nobel Lecture) (pages 1690–1696)

      Martin Evans

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800352

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      The story of mouse ES cells: Here, Martin Evans discusses the studies which led up to the discovery of mouse ES cells and their use for experimental mammalian egnetics, initially exemplified by using retroviral vectors. ES cells allow new, specifically targeted mutations to be tested in the context of the whole animal. ES cells are shown to be identical to a cell type in the normal mouse embryo. This work was honoured with the 2007 Nobel Prize for Physiology or Medicine

  5. Highlight

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Highlight
    7. Communications
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    1. Tryptophan π-Electron System Capping a Copper(I) Binding Site—A New Organometallic Bonding Mode in Proteins (pages 1697–1699)

      Olaf Kühl and Winfried Hinrichs

      Article first published online: 12 JUN 2008 | DOI: 10.1002/cbic.200800252

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      η2-Arene coordination (dotted lines) from the aromatic tryptophan side chain to CuI (red) in the prokaryotic CuI-transport protein CusF represents a new organometallic interaction in biology.

  6. Communications

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    3. Graphical Abstract
    4. News
    5. Review
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    7. Communications
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    1. Peptide Tertiary Structure Nucleation by Side-Chain Crosslinking with Metal Complexation and Double “Click” Cycloaddition (pages 1701–1705)

      Oscar Torres, Deniz Yüksel, Matt Bernardina, Krishna Kumar and Dennis Bong

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800040

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      Dimerization assist: Folding-incompetent peptides are restored to dimerization capability by side-chain crosslinking using both Ni2+–histidine complexation and a novel double “click” cycloaddition between the i and i+4 azidoalanine residues and synthetic bisalkyne linkers.

    2. Glycotripod Amphiphiles for Solubilization and Stabilization of a Membrane-Protein Superassembly: Importance of Branching in the Hydrophilic Portion (pages 1706–1709)

      Pil S. Chae, Marc J. Wander, Aaron P. Bowling, Philip D. Laible and Samuel H. Gellman

      Article first published online: 24 JUN 2008 | DOI: 10.1002/cbic.200800169

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      Three-legged friends: Intrinsic membrane proteins must usually be extracted from the native membrane with the aid of synthetic amphiphiles and then stabilized before detailed structural and functional characterization is possible. We describe new amphiphiles with unusual architectures that were useful for extraction and stabilization of protein superassemblies from bacterial membranes. Our results suggest that incorporation of branch points (as shown in figure) in both the hydrophilic and lipophilic portions can lead to favorable amphiphile behavior.

    3. Synergistic Actions of a Monooxygenase and Cyclases in Aromatic Polyketide Biosynthesis (pages 1710–1715)

      Jixun Zhan, Kenji Watanabe and Yi Tang

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800178

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      Synergistic tailoring: Formation of the pentangular aglycon of pradimicin A requires the synergistic actions of the monooxygenase PdmH, which hydroxylates ring B, and the two cyclases PdmK and PdmL. Removal of any one of three enzymes resulted in the biosynthesis of shunt products that are not properly oxidized and cyclized. The concerted actions of the enzymes may serve as a mechanism to suppress spontaneous cyclization of the extended dodecaketide backbone.

    4. Chemical Synthesis and Immunological Properties of Oligosaccharides Derived from the Vegetative Cell Wall of Bacillus anthracis (pages 1716–1720)

      Mahalakshmi Vasan, Jana Rauvolfova, Margreet A. Wolfert, Christine Leoff, Elmar L. Kannenberg, Conrad P. Quinn, Russell W. Carlson and Geert-Jan Boons

      Article first published online: 18 JUN 2008 | DOI: 10.1002/cbic.200800210

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      Sweet relief: Sera from rabbits exposed to Bacillus anthracis Sterne 34F2 spores or immunized with B. anthracis polysaccharide conjugated to keyhole limpet hemocyanin were found to contain antibodies that recognized isolated polysaccharide (shown) and two synthetic trisaccharides. This provides proof-of-concept towards the development of vegetative and spore-specific reagents for detection and targeting of nonprotein structures of B. anthracis.

    5. Inhibition of Cathepsin L by Epoxysuccinyl Peptides Simultaneously Addressing Active-Site and Remote-Site Regions (pages 1721–1724)

      Norbert Schaschke, Irmgard Assfalg-Machleidt and Werner Machleidt

      Article first published online: 13 JUN 2008 | DOI: 10.1002/cbic.200800103

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      The propeptide domain as structural guide: Based on information provided by the cathepsin L prodomain, a remote-site region was identified and exploited to improve the affinity/selectivity profile of irreversible cathepsin L inhibitors.

    6. Peptide Backbone Mutagenesis of Putative Gating Hinges in a Potassium Ion Channel (pages 1725–1728)

      Yasuo Nagaoka, Lijun Shang, Arijit Banerjee, Hagan Bayley and Stephen J. Tucker

      Article first published online: 9 JUN 2008 | DOI: 10.1002/cbic.200800133

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      Who's the gatekeeper? The mechanism by which K+ channels open and close or “gate” is still not fully understood. In this study, we use unnatural amino acid mutagenesis to change the flexibility of the pore-lining helices of the Kir2.1 potassium channel at two key glycine residues that have been implicated in channel gating.

    7. Smart Magnetic Resonance Imaging Agents that Sense Extracellular Calcium Fluctuations (pages 1729–1734)

      Goran Angelovski, Petra Fouskova, Ilgar Mamedov, Santiago Canals, Eva Toth and Nikos K. Logothetis

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800165

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      Image brain function: Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain. Upon interaction with Ca2+, they exhibit high and reversible relaxivity changes in buffered solution or in a model of the brain extracellular medium. These efficient Ca2+ magnetic resonance imaging sensors might open new perspectives in functional molecular imaging.

    8. Azido-BODIPY Acid Reveals Quantitative Staudinger–Bertozzi Ligation in Two-Step Activity-Based Proteasome Profiling (pages 1735–1738)

      Martijn Verdoes, Bogdan I. Florea, Ulrik Hillaert, Lianne I. Willems, Wouter A. van der Linden, Myra Sae-Heng, Dmitri V. Filippov, Alexei F. Kisselev, Gijsbert A. van der Marel and Herman S. Overkleeft

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800231

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      Flexibility in protein profiling: Employing the new bifunctional fluorophore azido-BODIPY acid we have synthesized a compatible set of one-step and two-step proteasome probes and demonstrate that with these the efficiency of the Staudinger–Bertozzi ligation in the two-step activity-based protein profiling of the proteasome catalytic activities is easily established.

  7. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Highlight
    7. Communications
    8. Full Papers
    9. Preview
    1. Zn2+ Complexes of Di- and Tri-nucleating Azacrown Ligands as Base-Moiety-Selective Cleaving Agents of RNA 3′,5′-Phosphodiester Bonds: Binding to Guanine Base (pages 1739–1748)

      Qi Wang, Ewelina Leino, Attila Jancsó, István Szilágyi, Tamás Gajda, Emilia Hietamäki and Harri Lönnberg

      Article first published online: 23 JUN 2008 | DOI: 10.1002/cbic.200800095

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      Guanine works too: The ability of the dinuclear Zn2+ complex of 1,4-bis[(1,5,9-triazacyclododecan-3-yloxy)methyl]benzene (L1) to promote the cleavage of the phosphodiester bond of dinucleoside-3′,5′-monophosphates that contain a guanine base has been studied over a narrow pH range from 5.8 to 7.2 at 90 °C. Di- and trinuclear Zn2+ complexes of azacrown-derived ligands recognize a guanine base, though less efficiently than a uracil base.

    2. Exploring the Conserved Water Site and Hydration of a Coiled-Coil Trimerisation Motif: A MD Simulation Study (pages 1749–1756)

      Jožica Dolenc, Riccardo Baron, John H. Missimer, Michel O. Steinmetz and Wilfred F. van Gunsteren

      Article first published online: 13 JUN 2008 | DOI: 10.1002/cbic.200800096

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      Water bridges: The solvent structure and dynamics around ccβ-p, a 17-residue peptide that forms a three-stranded α-helical coiled coil in solution, was analysed by using molecular dynamics simulations. Pronounced peaks in the solvent density distribution between residues Arg8 and Glu13 of neighbouring helices show the presence of water bridges, in agreement with the water sites that were observed in X-ray crystallography experiments.

    3. Benzene Polyphosphates as Tools for Cell Signalling: Inhibition of Inositol 1,4,5-Trisphosphate 5-Phosphatase and Interaction with the PH Domain of Protein Kinase Bα (pages 1757–1766)

      Stephen J. Mills, Fabrice Vandeput, Melanie N. Trusselle, Stephen T. Safrany, Christophe Erneux and Barry V. L. Potter

      Article first published online: 23 JUN 2008 | DOI: 10.1002/cbic.200800104

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      Benzene polyphosphates, which are emerging as new cell signalling tools, were synthesised and evaluated as inhibitors of type I Ins(1,4,5)P3 5-phosphatase and of the pleckstrin homology (PH) domain of protein kinase Bα (PKBα). Biphenyl 2,3′,4,5′,6-pentakisphosphate exhibits a low nanomolar Ki value at the PH domain of PKBα.

    4. An Indole-Binding Site is a Major Determinant of the Ligand Specificity of the GABA Type A Receptor-Associated Protein GABARAP (pages 1767–1775)

      Yvonne Thielmann, Jeannine Mohrlüder, Bernd W. Koenig, Thomas Stangler, Rudolf Hartmann, Karin Becker, Hans-Dieter Höltje and Dieter Willbold

      Article first published online: 20 JUN 2008 | DOI: 10.1002/cbic.200800117

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      Precious tryptophan: Binding partners of GABAA receptor associated protein (GABARAP) feature a conserved tryptophan. NMR spectroscopy studies on the GABARAP binding of indole and indole derivatives allowed us to distinguish two tryptophan-binding pockets with different ligand affinities (see figure). Analysis of the GABARAP–tryptophan interaction was based on experimental and bioinformatics approaches.

    5. Catalyzed Oxidative Corrosion of Porous Silicon Used as an Optical Transducer for Ligand–Receptor Interactions (pages 1776–1786)

      Nicolas H. Voelcker, Ignacio Alfonso and M. Reza Ghadiri

      Article first published online: 24 JUN 2008 | DOI: 10.1002/cbic.200800119

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      Corrosive influence: We demonstrate that a nickel(II)cyclam catalyst can rapidly corrode porous silicon films, thereby affording a strong optical interferometric signal originating from the porous layer. By conjugating the catalyst moiety to ligands such as DNA oligonucleotides or biotin, we employ this phenomenon in the proof-of-principle of an optical transducer for ligand–receptor interactions.

    6. Modular Assembly Using Sequential Palladium Coupling Gives Easy Access to the SMoC Class of Cellular Transporters (pages 1787–1796)

      Anne-Sophie Rebstock, Cristina Visintin, Elisabetta Leo, Cristina Garcia Posada, Sarah R. Kingsbury, Gareth H. Williams, Kai Stoeber and David L. Selwood

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800153

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      Have a lift: The transducing ability of the third helix of transcription factor homeodomains is effectively mimicked by a biphenyl system displaying guanidine groups (see scheme). The biphenyl class of small-molecule carriers (SMoCs) can carry biomolecules into a wide variety of cell types. A “combinatorial” approach to the synthesis of SMoCs is described using sequential Pd0 coupling chemistry to assemble the molecules from highly functionalized building blocks.

    7. Addressing the Numbers Problem in Directed Evolution (pages 1797–1804)

      Manfred T. Reetz, Daniel Kahakeaw and Renate Lohmer

      Article first published online: 20 JUN 2008 | DOI: 10.1002/cbic.200800298

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      The optimal choice of codon degeneracy when performing knowledge-guided saturation mutagenesis allows for smaller amino acid alphabets, thus resulting in higher-quality enzyme libraries. By comparing NNK with NDT libraries in the directed evolution of an enantioselective epoxide hydrolase (shown), we conclude that the number of codons should be equal to the number of amino acids as building blocks.

    8. Application of Metal-Free Triazole Formation in the Synthesis of Cyclic RGD–DTPA Conjugates (pages 1805–1815)

      Sander S. van Berkel, A. (Ton) J. Dirks, Silvie A. Meeuwissen, Dennis L. L. Pingen, Otto C. Boerman, Peter Laverman, Floris L. van Delft, Jeroen J. L. M. Cornelissen and Floris P. J. T. Rutjes

      Article first published online: 11 JUL 2008 | DOI: 10.1002/cbic.200800074

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      The trick, a metal-free click! No transition metal catalyst is necessary for the formation of triazole containing conjugates when utilizing the tandem cycloaddition-retro-Diels–Alder (crDA) reaction. Optimization of the tandem crDA reaction led to the selective formation of a c(RGD)-CF3-triazole-DTPA conjugate, showing a good IC50 value and favorable hydrophilicity in preliminary biological studies.

    9. Synthesis, Conformation, and Activity of Human Insulin-Like Peptide 5 (INSL5) (pages 1816–1822)

      Mohammed Akhter Hossain, Ross A. D. Bathgate, Chze K. Kong, Fazel Shabanpoor, Suode Zhang, Linda M. Haugaard-Jönsson, K. Johan Rosengren, Geoffrey W. Tregear and John D. Wade

      Article first published online: 24 JUN 2008 | DOI: 10.1002/cbic.200800113

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      Ready for a shot: The A and B chains of human insulin-like peptide 5 (INSL5) are “difficult sequences”, however, we managed to successfully prepare these by SPPS after protocol modification. Use of regioselective cysteine thiol protecting groups allowed subsequent sequential disulfide bond formation and chain combination. The resulting synthetic INSL5 was obtained in good overall yield and will be a valuable tool in determining its biological function.

    10. Dynamic Combinatorial Self-Assembly of Cyclophilin hCyp-18 Ligands through Oxorhenium Coordination (pages 1823–1829)

      Cécile Clavaud, Julien Le Gal, Robert Thai, Mireille Moutiez and Christophe Dugave

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800187

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      What′re your coordinates? The dynamic combinatorial assembly of independent modules A and B as a result of oxorhenium(V) coordination was investigated in the presence of cyclophilin hCyp-18. Increasing glutathione concentration was used to dissociate [A⋅ReVO⋅B] complexes that displayed low affinity for hCyp-18. Conversely, coordinates that displayed submicromolar affinities for hCyp-18 were protected against thiol exchange and could be detected by LC-MS.

    11. Rhizobium rubiT: A Gram-Negative Phytopathogenic Bacterium Expressing the Lewis B Epitope on the Outer Core of its Lipooligosaccharide Fraction (pages 1830–1835)

      Valentina Gargiulo, Domenico Garozzo, Rosa Lanzetta, Antonio Molinaro, Luisa Sturiale, Cristina De Castro and Michelangelo Parrilli

      Article first published online: 23 JUN 2008 | DOI: 10.1002/cbic.200800191

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      Camouflage? The mammalian blood group antigen Lewis B has been found for the first time in the lipooligosaccharide (LOS) of the phytopathogenic bacterium Rhizobium rubi (see graphic). The structure of this LOS was determined by chemical analysis, mass spectrometry and NMR spectroscopy. The two main oligosaccharides that were isolated differ in the occurrence of a terminal α-GalA residue on the external Kdo unit, but possess the same antigenic appendage.

    12. Multivalent Carbohydrate Recognition on a Glycodendrimer-Functionalized Flow-Through Chip (pages 1836–1844)

      Hilbert M. Branderhorst, Rob Ruijtenbeek, Rob M. J. Liskamp and Roland J. Pieters

      Article first published online: 4 JUL 2008 | DOI: 10.1002/cbic.200800195

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      Does it stick? Glycodendrimers on a flow-through chip allow real-time evaluation of multivalency effects in protein–carbohydrate interactions in a single experiment. Furthermore, kinetic and thermodynamic data on binding events can be deduced, and inhibition experiments are also possible.

  8. Preview

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    3. Graphical Abstract
    4. News
    5. Review
    6. Highlight
    7. Communications
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      Preview: ChemBioChem 12/2008 (page 1850)

      Article first published online: 11 JUL 2008 | DOI: 10.1002/cbic.200890043

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