Human integrin alphavbeta5: homology modeling and ligand binding

The recently reported crystal structures of the extracellular domains of the alphavbeta3 integrin in its unligated state and in complex with the peptide cyclo(-RGDf[NMe]V-) have dramatically increased our understanding of ligand binding to integrins. Nonetheless, ligand selectivity toward different integrin subtypes is still a challenging problem complicated by the fact that 3D structures of most of the integrin subtypes remain unknown. In this study, a three-dimensional model for the human alphavbeta5 integrin was obtained using homology modeling based on the crystal coordinates of alphavbeta3 in its bound conformation as template. The modeled receptor was refined using energy minimization and molecular dynamics simulations in explicit solvent. The refined alphavbeta5 model was used to explore the interactions between this integrin and alphavbeta3/alphavbeta5 dual and alphavbeta3-selective ligands in the attempt to provide a preliminary rationalization, at the molecular level, of ligand selectivity toward the two alphav integrins. It was found that, in the RGD binding site of the alphavbeta5 receptor, a partial "roof" composed mainly of the SDL residues Tyr179 and Lys180 is present and hampers the binding of compounds containing bulky substituents in the proximity of the carboxylate group. This study provides a testable hypothesis for alphav integrins subtype ligand binding selectivity, in line with both mutagenesis data and SARs studies.