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- Title
Structural basis for pure antagonism of integrin α<sub>V</sub>β<sub>3</sub> by a high-affinity form of fibronectin.
- Authors
Van Agthoven, Johannes F; Xiong, Jian-Ping; Alonso, José Luis; Rui, Xianliang; Adair, Brian D; Goodman, Simon L; Arnaout, M Amin
- 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 tenth type III RGD domain of wild-type fibronectin (wtFN10), or to a high-affinity mutant (hFN10) shown here to act 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. These findings offer new insights into the mechanism of integrin activation and a basis for the design of RGD-based pure antagonists.
- Publication
Nature Structural & Molecular Biology, 2014, Vol 21, Issue 4, p383
- ISSN
1545-9993
- Publication type
Academic Journal
- DOI
10.1038/nsmb.2797