4MMZ: Integrin AlphaVBeta3 ectodomain bound to an antagonistic tenth domain of Fibronectin

Citation:
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 alphaVbeta3 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 pi-pi interaction between Trp1496 in the RGD-containing loop of hFN10 and Tyr122 of the beta3 subunit that blocked conformational changes triggered by wtFN10 and trapped hFN10-bound alphaVbeta3 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.
PDB ID: 4MMZDownload
MMDB ID: 118614
PDB Deposition Date: 2013/9/9
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 3.102  Å
Source Organism:
Similar Structures:
Biological Unit for 4MMZ: trimeric; determined by author
Molecular Components in 4MMZ
Label Count Molecule
Proteins (3 molecules)
1
Integrin Alpha-v(Gene symbol: ITGAV)
Molecule annotation
1
Integrin Beta-3(Gene symbol: ITGB3)
Molecule annotation
1
Fibronectin(Gene symbol: FN1)
Molecule annotation
Chemicals (38 molecules)
1
19
2
3
3
2
4
8
5
2
6
2
7
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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