High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design

Antonella Paladino; Monica Civera; Laura Belvisi; Giorgio Colombo

doi:10.1371/journal.pcbi.1005334

High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design

PLoS Comput Biol. 2017 Jan 23;13(1):e1005334. doi: 10.1371/journal.pcbi.1005334. eCollection 2017 Jan.

Authors

Antonella Paladino¹, Monica Civera², Laura Belvisi², Giorgio Colombo¹

Affiliations

¹ Istituto di Chimica del Riconoscimento Molecolare CNR, Milan, Italy.
² Dipartimento di Chimica, Università degli Studi di Milano, Milan, Italy.

Abstract

Understanding how binding events modulate functional motions of multidomain proteins is a major issue in chemical biology. We address several aspects of this problem by analyzing the differential dynamics of αvβ3 integrin bound to wild type (wtFN10, agonist) or high affinity (hFN10, antagonist) mutants of fibronectin. We compare the dynamics of complexes from large-scale domain motions to inter-residue coordinated fluctuations to characterize the distinctive traits of conformational evolution and shed light on the determinants of differential αvβ3 activation induced by different FN sequences. We propose an allosteric model for ligand-based integrin modulation: the conserved integrin binding pocket anchors the ligand, while different residues on the two FN10's act as the drivers that reorganize relevant interaction networks, guiding the shift towards inactive (hFN10-bound) or active states (wtFN10-bound). We discuss the implications of results for the design of integrin inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Drug Discovery / methods*
Fibronectins / chemistry*
Fibronectins / ultrastructure*
Integrin alphaVbeta3 / chemistry*
Integrin alphaVbeta3 / ultrastructure*
Models, Chemical
Molecular Dynamics Simulation*
Protein Binding
Protein Conformation
Protein Domains

Substances

Fibronectins
Integrin alphaVbeta3

Grants and funding

This work was supported by Ministero dell’Università e della Ricerca PRIN project 2010NRREPL; PRIN project 20157WW5EH to LB and GC; and Associazione Italiana Ricerca sul Cancro IG 15420 to GC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.