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

Nat Struct Mol Biol. 2014 Apr;21(4):383-8. doi: 10.1038/nsmb.2797. Epub 2014 Mar 23.


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 types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Cell Adhesion
  • Crystallography, X-Ray
  • Fibronectins / chemistry*
  • Fibronectins / metabolism
  • Humans
  • Integrin alphaVbeta3 / chemistry*
  • Integrin alphaVbeta3 / metabolism
  • Integrin alphaVbeta3 / physiology
  • Models, Molecular
  • Protein Structure, Tertiary


  • Fibronectins
  • Integrin alphaVbeta3

Associated data

  • PDB/4MMX
  • PDB/4MMY
  • PDB/4MMZ