The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin αvβ3. Issue 23 (28th March 2019)

• Record Type: Journal Article
• Authors: Paladino, Antonella; Civera, Monica; Curnis, Flavio; Paolillo, Mayra; Gennari, Cesare; Piarulli, Umberto; Corti, Angelo; Belvisi, Laura; Colombo, Giorgio
• Is Part Of: Chemistry. Volume 25:Issue 23(2019)
• Page Start: 5959
• Page End: 5970
• Publication Date: 2019-03-28
• Subjects: conformation analysis -- flow cytometry analysis -- molecular dynamics -- peptidomimetics -- proteins; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201900169
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Ligand‐based control of protein functional motions can provide novel opportunities in the study of fundamental biological mechanisms and in the development of novel therapeutics. In this work we addressed the ligand‐based modulation of integrin functions. Inhibitors of integrin αv β3 are interesting anticancer agents but their molecular mechanisms are still unclear: Peptides and peptidomimetics characterized by the Arg‐Gly‐Asp (RGD) or isoAsp‐Gly‐Arg (isoDGR) binding motifs have shown controversial agonist/antagonist effects. We have investigated the differential mechanisms of integrin activation/deactivation by three distinct ligands ( cyclo ‐RGDf(NMe)V (Cilengitide), cyclo [DKP3‐RGD], cyclo [DKP3‐isoDGR]; DKP=diketopiperazine) through a comparative analysis of ligand‐controlled protein internal dynamics: Although RGD facilitates the onset of dynamic states leading to activation, isoDGR induces a diffuse rigidification of the complex consistent with antagonist activities. Computational predictions have been experimentally probed by showing that the antibody AP5, which is capable of recognizing the active form of integrin, binds specifically to the RGD complexes and not to the isoDGR complex, which supports opposite functional roles of the two motifs targeting the same binding site. Abstract : Integrin (de)activation : The electrostatic clamp at the binding site and the ability of the ligands to create different hydrophobic locks on the surface of one of the subdomains of integrin translate into the modulation of integrin dynamics selecting opening versus closing motions (see figure).