title: High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design.
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.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare CNR, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Paladino
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Civera
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare CNR, Milan, Italy.
authors.forename: Giorgio
authors.identifier: 0000-0002-1318-668X
authors.initials: G
authors.lastname: Colombo
mesh_terms: D001665:Binding Sites; D055808:Drug Discovery / Q000379:methods*; D005353:Fibronectins / Q000737:chemistry* / Q000648:ultrastructure*; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains
chemical_list: D005353:Fibronectins; D039302:Integrin alphaVbeta3