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  • 1
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    Type IIA topoisomerase inhibition by a new class of antibacterial agents (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-08-06
    Description: Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bax, Benjamin D -- Chan, Pan F -- Eggleston, Drake S -- Fosberry, Andrew -- Gentry, Daniel R -- Gorrec, Fabrice -- Giordano, Ilaria -- Hann, Michael M -- Hennessy, Alan -- Hibbs, Martin -- Huang, Jianzhong -- Jones, Emma -- Jones, Jo -- Brown, Kristin Koretke -- Lewis, Ceri J -- May, Earl W -- Saunders, Martin R -- Singh, Onkar -- Spitzfaden, Claus E -- Shen, Carol -- Shillings, Anthony -- Theobald, Andrew J -- Wohlkonig, Alexandre -- Pearson, Neil D -- Gwynn, Michael N -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Aug 19;466(7309):935-40. doi: 10.1038/nature09197. Epub 2010 Aug 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. benjamin.d.bax@gsk.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686482" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/*chemistry/metabolism/*pharmacology ; Apoenzymes/chemistry/metabolism ; Arginine/metabolism ; Aspartic Acid/metabolism ; Binding Sites ; Catalytic Domain ; Ciprofloxacin/chemistry/metabolism ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA Cleavage ; DNA Gyrase/*chemistry/metabolism ; DNA, Superhelical/chemistry/metabolism ; Drug Design ; Drug Resistance ; Escherichia coli/enzymology ; Manganese/metabolism ; Models, Molecular ; Protein Conformation ; Quinolines/*chemistry/metabolism/*pharmacology ; Quinolones/chemistry/metabolism ; Staphylococcus aureus/*enzymology ; Structure-Activity Relationship ; *Topoisomerase II Inhibitors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Switching from cut-and-paste to replicative Tn7 transposition (1996)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1996-04-19
    Description: The bacterial transposon Tn7 usually moves through a cut-and-paste mechanism whereby the transposon is excised from a donor site and joined to a target site to form a simple insertion. The transposon was converted to a replicative element that generated plasmid fusions in vitro and cointegrate products in vivo. This switch was a consequence of the separation of 5'- and 3'-end processing reactions of Tn7 transposition as demonstrated by the consequences of a single amino acid alteration in an element-encoded protein essential for normal cut-and-paste transposition. The mutation specifically blocked cleavage of the 5' strand at each transposon end without disturbing the breakage and joining on the 3' strand, producing a fusion (the Shapiro Intermediate) that resulted in replicative transposition. The ability of Tn7 recombination products to serve as substrates for both the limited gap repair required to complete cut-and-paste transposition and the extensive DNA replication involved in cointegrate formation suggests a remarkable plasticity in Tn7's recruitment of host repair and replication functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉May, E W -- Craig, N L -- New York, N.Y. -- Science. 1996 Apr 19;272(5260):401-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8602527" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/genetics/*metabolism ; DNA Repair ; *DNA Replication ; DNA Transposable Elements/*genetics ; DNA-Binding Proteins/genetics/*metabolism ; *Escherichia coli Proteins ; Mutagenesis, Site-Directed ; Plasmids ; Point Mutation ; *Recombination, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Characterizing Neutron-Proton Equilibration in Nuclear Reactions with Subzeptosecond Resolution (2017)
    American Physical Society (APS)
    Details
    Publication Date: 2017-02-14
    Description: Author(s): A. Jedele, A. B. McIntosh, K. Hagel, M. Huang, L. Heilborn, Z. Kohley, L. W. May, E. McCleskey, M. Youngs, A. Zarrella, and S. J. Yennello The equilibration of nuclei containing a large imbalance of protons and neutrons can occur in 3 × 10 − 22 seconds, according to experiments—important information for models of element-creation in supernovae. [Phys. Rev. Lett. 118, 062501] Published Fri Feb 10, 2017
    Keywords: Nuclear Physics
    Print ISSN: 0031-9007
    Electronic ISSN: 1079-7114
    Topics: Physics
    Published by American Physical Society (APS)
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  • 4
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    The Tn7 transposase is a heteromeric complex in which DNA breakage and joining activities are distributed between different gene products. (1996)
    EMBO Press
    Details
    Publication Date: 1996-11-01
    Print ISSN: 0261-4189
    Electronic ISSN: 1460-2075
    Topics: Biology , Medicine
    Published by EMBO Press on behalf of European Molecular Biology Organization.
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