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  • 1
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    Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-05-24
    Description: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEdelta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEdelta to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEdelta interaction that selectively bind to the prenyl-binding pocket of PDEdelta with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zimmermann, Gunther -- Papke, Bjorn -- Ismail, Shehab -- Vartak, Nachiket -- Chandra, Anchal -- Hoffmann, Maike -- Hahn, Stephan A -- Triola, Gemma -- Wittinghofer, Alfred -- Bastiaens, Philippe I H -- Waldmann, Herbert -- England -- Nature. 2013 May 30;497(7451):638-42. doi: 10.1038/nature12205. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698361" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/metabolism ; Animals ; Benzimidazoles/*chemistry/metabolism/*pharmacology/therapeutic use ; Binding Sites ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & ; inhibitors/chemistry/*metabolism ; Dogs ; Humans ; Hydrogen Bonding ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinases/metabolism ; Models, Molecular ; Molecular Conformation ; Neoplasm Transplantation ; Oncogene Protein p21(ras)/*antagonists & inhibitors/genetics/*metabolism ; Protein Binding/drug effects ; Signal Transduction/*drug effects
    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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    Revealing conformational substates of lipidated N-Ras protein by pressure modulation (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-12-27
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Revealing conformational substates of lipidated N-Ras protein by pressure modulation [Biophysics and Computational Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-01-12
    Description: Regulation of protein function is often linked to a conformational switch triggered by chemical or physical signals. To evaluate such conformational changes and to elucidate the underlying molecular mechanisms of subsequent protein function, experimental identification of conformational substates and characterization of conformational equilibria are mandatory. We apply pressure modulation in combination with FTIR spectroscopy to reveal equilibria between spectroscopically resolved substates of the lipidated signaling protein N-Ras. Pressure has the advantage that its thermodynamic conjugate is volume, a parameter that is directly related to structure. The conformational dynamics of N-Ras in its different nucleotide binding states in the absence and presence of a model biomembrane was probed by pressure perturbation. We show that not only nucleotide binding but also the presence of the membrane has a drastic effect on the conformational dynamics and selection of conformational substates of the protein, and a new substate appearing upon membrane binding could be uncovered. Population of this new substate is accompanied by structural reorientations of the G domain, as also indicated by complementary ATR-FTIR and IRRAS measurements. These findings thus illustrate that the membrane controls signaling conformations by acting as an effective interaction partner, which has consequences for the G-domain orientation of membrane-associated N-Ras, which in turn is known to be critical for its effector and modulator interactions. Finally, these results provide insights into the influence of pressure on Ras-controlled signaling events in organisms living under extreme environmental conditions as they are encountered in the deep sea where pressures reach the kbar range.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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