Conformational studies of RGDechi peptide by natural‐abundance NMR spectroscopy. (18th March 2019)

• Record Type: Journal Article
• Authors: Farina, Biancamaria; Del Gatto, Annarita; Comegna, Daniela; Di Gaetano, Sonia; Capasso, Domenica; Isernia, Carla; Saviano, Michele; Fattorusso, Roberto; Zaccaro, Laura; Russo, Luigi
• Other Names: Morelli Giancarlo guestEditor.
• Is Part Of: Journal of peptide science. Volume 25:Number 5(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-03-18
• Subjects: integrin -- natural‐abundance NMR -- recognition mechanism -- structure‐activity relationship; Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.3166
• Languages: English
• ISSNs: 1075-2617

Abstract

Abstract : Integrins are heterodimeric cell‐surface proteins that play important roles during developmental and pathological processes. Diverse human pathologies involve integrin adhesion including thrombotic diseases, inflammation, tumour progression, fibrosis, and infectious diseases. Although in the past decade, novel integrin‐inhibitor drugs have been developed for integrin‐based medical applications, the structural determinants modulating integrin‐ligands recognition mechanisms are still poorly understood, reducing the number of integrin subtype exclusive antagonists. In this scenario, we have very recently showed, by means of chemical and biological assays, that a chimeric peptide (named RGDechi), containing a cyclic RGD motif linked to an echistatin C‐terminal fragment, is able to interact with the components of integrin family with variable affinities, the highest for αv β3. Here, in order to understand the mechanistic details driving the molecular recognition mechanism of αv β3 by RGDechi, we have performed a detailed structural and dynamics characterization of the free peptide by natural abundance nuclear magnetic resonance (NMR) spectroscopy. Our data indicate that RGDechi presents in solution an heterogeneous conformational ensemble characterized by a more constrained and rigid pentacyclic ring and a largely unstructured acyclic region. Moreover, we propose that the molecular recognition of αv β3 integrin by RGDechi occurs by a combination of conformational selection and induced fit mechanisms. Finally, our study indicates that a detailed NMR characterization, by means of natural abundance 15 N and 13 C, of a mostly unstructured bioactive peptide may provide the molecular basis to get essential structural insights into the binding mechanism to the biological partner. Abstract : In this study, we performed a structural and dynamics characterization of the RGDechi peptide by natural abundance NMR spectroscopy. Our findings demonstrate that RGDechi explores a heterogeneous conformational ensemble characterized by a more constrained and rigid pentacyclic ring and a largely unstructured acyclic region. Additionally, one possible scenario for the molecular mechanism, driving the recognition of αvβ3 integrin by RGDechi, is proposed.