Molecular Model of the α_IIbβ₃ Integrin

A molecular model of the αIIbβ3 integrin has been developed utilizing (i) the crystal structure of αvβ3, (ii) homology model of the αIIb subdomain, and (iii) the docking of αIIbβ3/αvβ3 dual and selective inhibitors into the putative binding sites of αIIbβ3 and αvβ3. Since the binding sites of these integrins are located at the interface between the two heads of the individual subunits, only the αIIbβ3 head region is modeled. The 3D conformations of two loops in αIIb, whose residues have been implicated in non-peptide ligand binding, could not be determined from homology with αv alone. Mutagenesis data and the modeling of small ligand binding contributed to the rational design of these loop conformations. The final energy minimized loop conformations exhibit permissible φ/ψ angles and contribute to a binding site model of αIIbβ3 that is consistent with both the known mutagenesis studies and in-house structure−activity relationships. The charged residues αIIb:E117 and β3:R214 are found to dominate the ligand−protein binding interaction. The previously identified “exosite” is also identified as a hydrogen bond, hydrophobic or π−π interaction with Y190, similar to the recently proposed binding model of αvβ3.