The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin αv β3

Chemistry : a European Journal
Antonella PaladinoGiorgio Colombo

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 role...Continue Reading

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Citations

Sep 15, 2020·Expert Opinion on Drug Discovery·Dermot Cox
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Silvia PanzeriUmberto Piarulli
Apr 2, 2021·Journal of Chemical Information and Modeling·Antonella PaladinoMichele Ceccarelli
Jul 2, 2021·Biophysical Journal·Jazmin OzsvarAnthony S Weiss

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