Mapping of heparin/heparan sulfate binding sites on αvβ3 integrin by molecular docking.

Heparin/heparan sulfate interact with growth factors, chemokines, extracellular proteins, and receptors. Integrins are αβ heterodimers that serve as receptors for extracellular proteins, regulate cell behavior, and participate in extracellular matrix assembly. Heparin binds to RGD-dependent integrins (αIIbβ3, α5β1, αvβ3, and αvβ5) and to RGD-independent integrins (α4β1, αXβ2, and αMβ2), but their binding sites have not been located on integrins. We report the mapping of heparin binding sites on the ectodomain of αvβ3 integrin by molecular modeling. The surface of the ectodomain was scanned with small rigid probes mimicking the sulfated domains of heparan sulfate. Docking results were clustered into binding spots. The best results were selected for further docking simulations with heparin hexasaccharide. Six potential binding spots containing lysine and/or arginine residues were identified on the ectodomain of αvβ3 integrin. Heparin would mostly bind to the top of the genu domain, the Calf-I domain of the α subunit, and the top of the β subunit of RGD-dependent integrins. Three spots were close enough from each other on the integrin surface to form an extended binding site that could interact with heparin/heparan sulfate chains. Because heparin does not bind to the same integrin site as protein ligands, no steric hindrance prevents the formation of ternary complexes comprising the integrin, its protein ligand, and heparin/heparan sulfate. The basic amino acid residues predicted to interact with heparin are conserved in the sequences of RGD-dependent but not of RGD-independent integrins suggesting that heparin/heparan sulfate could bind to different sites on these two integrin subfamilies. Copyright © 2013 John Wiley & Sons, Ltd.

Citation

Lionel Ballut, Nicolas Sapay, Emilie Chautard, Anne Imberty, Sylvie Ricard-Blum. Mapping of heparin/heparan sulfate binding sites on αvβ3 integrin by molecular docking. Journal of molecular recognition : JMR. 2013 Feb;26(2):76-85

PMID: 23334915

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