van Agthoven, JohannesXiong, Jian-PingAlonso, JoseRui, XianliangAdair, BrianGoodman, Simon L.Arnaout, M.2014-11-032014Van 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.2797.1545-9993http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347584Integrins 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.en-USJournal Article2014-11-0310.1038/nsmb.2797