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

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

Author information

  • 11] Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2].
  • 2Leukocyte Biology and Inflammation Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
  • 3Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
  • 4Global Research and Early Development, Translational Innovation Platform, Oncology, Merck KGaA, Darmstadt, Germany.
  • 51] Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2] Leukocyte Biology and Inflammation Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

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.

PMID:
24658351
[PubMed - indexed for MEDLINE]
PMCID:
PMC4012256
Free PMC Article
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