A Combined NMR and Computational Approach to Determine the RGDechi‐hCit‐αvβ3 Integrin Recognition Mode in Isolated Cell Membranes |
| |
Authors: | Dr Biancamaria Farina Dr Ivan de Paola Dr Luigi Russo Dr Domenica Capasso Dr Annamaria Liguoro Dr Annarita Del Gatto Dr Michele Saviano Prof Paolo V Pedone Dr Sonia Di Gaetano Dr Gaetano Malgieri Dr Laura Zaccaro Prof Roberto Fattorusso |
| |
Institution: | 1. Dipatimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi Napoli, Via Vivaldi 46, 81100, Caserta (Italy);2. Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy);3. Dipartimento di Farmacia, Università di Napoli Federico II, Via Mezzocannone 16, 80134 Naples (Italy);4. Istituto di Cristallografia, CNR, Via Amendola 122/O, 70126 Bari (Italy) |
| |
Abstract: | The critical role of integrins in tumor progression and metastasis has stimulated intense efforts to identify pharmacological agents that can modulate integrin function. In recent years, αvβ3 and αvβ5 integrin antagonists were demonstrated to be effective in blocking tumor progression. RGDechi‐hCit, a chimeric peptide containing a cyclic RGD motif linked to an echistatin C‐terminal fragment, is able to recognize selectively αvβ3 integrin both in vitro and in vivo. High‐resolution molecular details of the selective αvβ3 recognition of the peptide are certainly required, nonetheless RGDechi‐hCit internalization limited the use of classical in cell NMR experiments. To overcome such limitations, we used WM266 isolated cellular membranes to accomplish a detailed NMR interaction study that, combined with a computational analysis, provides significant structural insights into αvβ3 molecular recognition by RGDechi‐hCit. Remarkably, on the basis of the identified molecular determinants, we design a RGDechi‐hCit mutant that is selective for αvβ5 integrin. |
| |
Keywords: | integrin cell membranes molecular docking NMR spectroscopy RGD ligand |
|
|