Structural basis for pure antagonism of integrin αVβ3 by a high affinity form of fibronectin

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Structural basis for pure antagonism of integrin αVβ3 by a high affinity form of fibronectin

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Title: Structural basis for pure antagonism of integrin αVβ3 by a high affinity form of fibronectin
Author: Van Agthoven, Johannes F.; Xiong, Jian-Ping; Alonso, José Luis; Rui, Xianliang; Adair, Brian D.; Goodman, Simon L.; Arnaout, M. Amin

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Citation: Van Agthoven, Johannes F., Jian-Ping Xiong, José Luis Alonso, Xianliang Rui, Brian D. Adair, Simon L. Goodman, and M. Amin Arnaout. 2014. “Structural basis for pure antagonism of integrin αVβ3 by a high affinity form of fibronectin.” Nature structural & molecular biology 21 (4): 383-388. doi:10.1038/nsmb.2797. http://dx.doi.org/10.1038/nsmb.2797.
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Abstract: Integrins are important therapeutic targets. However, current RGD-based anti-integrin drugs are also partial agonists, inducing conformational changes that trigger potentially fatal immune reactions and paradoxical cell adhesion. Here we describe the first crystal structure of αVβ3 bound to a physiologic ligand: the 10th type III RGD-domain of wild-type fibronectin (wtFN10), or to a high affinity mutant (hFN10) that acts as a pure antagonist. Comparison of these structures revealed a central π - π interaction between Trp1496 in the RGD-containing loop of hFN10 and Tyr122 of the β3-subunit that blocked conformational changes triggered by wtFN10, and trapped hFN10-bound αVβ3 in an inactive conformation. Removing the Trp1496 or Tyr122 side-chains, or reorienting Trp1496 away from Tyr122, converted hFN10 into a partial agonist. The findings offer new insights on the mechanism of integrin activation and a basis for design of RGD-based pure antagonists.
Published Version: doi:10.1038/nsmb.2797
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012256/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347584
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