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High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design
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) muta...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293283/ https://www.ncbi.nlm.nih.gov/pubmed/28114375 http://dx.doi.org/10.1371/journal.pcbi.1005334 |
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author | Paladino, Antonella Civera, Monica Belvisi, Laura Colombo, Giorgio |
author_facet | Paladino, Antonella Civera, Monica Belvisi, Laura Colombo, Giorgio |
author_sort | Paladino, Antonella |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5293283 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-52932832017-02-17 High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design Paladino, Antonella Civera, Monica Belvisi, Laura Colombo, Giorgio PLoS Comput Biol Research Article 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. Public Library of Science 2017-01-23 /pmc/articles/PMC5293283/ /pubmed/28114375 http://dx.doi.org/10.1371/journal.pcbi.1005334 Text en © 2017 Paladino et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Paladino, Antonella Civera, Monica Belvisi, Laura Colombo, Giorgio High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design |
title | High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design |
title_full | High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design |
title_fullStr | High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design |
title_full_unstemmed | High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design |
title_short | High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design |
title_sort | high affinity vs. native fibronectin in the modulation of αvβ3 integrin conformational dynamics: insights from computational analyses and implications for molecular design |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293283/ https://www.ncbi.nlm.nih.gov/pubmed/28114375 http://dx.doi.org/10.1371/journal.pcbi.1005334 |
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