Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy,in silico and in vivo Studies |
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| Authors: | Dr Demetra S M Chatzileontiadou Aikaterini C Tsika Dr Zoi Diamantopoulou Prof Jean Delbé Prof Josette Badet Prof José Courty Dr Vassiliki T Skamnaki Dr Vanessa Parmenopoulou Prof Dimitri Komiotis Dr Joseph M Hayes Prof Georgios A Spyroulias Prof Demetres D Leonidas |
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| Affiliation: | 1. Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, Larissa, Greece;2. Current address: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Australia;3. Department of Pharmacy, University of Patras, Patras, Greece;4. Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Université Paris–EST Créteil, CNRS ERL 9215, France;5. Current address: Cancer Research (UK) Manchester Institute, Manchester, UK;6. INSERM U1139, Université Paris Descartes, Paris, France;7. Centre for Materials Science and School of Physical Sciences & Computing, University of Central Lancashire, Preston, UK |
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| Abstract: | A member of the ribonuclease A superfamily, human angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced‐fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modeling suggests the potential for simultaneous binding of the inhibitors at the active and cell‐binding sites, NMR studies indicate greater affinity for the cell‐binding site than for the active site. Additionally, molecular dynamics simulations at 100 ns confirmed the stability of binding at the cell‐binding site with the predicted protein–ligand interactions, in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to completely inhibit the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and its ribonucleolytic activity. |
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| Keywords: | angiogenesis NMR spectroscopy nucleosides RNase triazoles |
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