The recently reported crystal structures of the extracellular domains of the avb3 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 threedimensional model for the human avb5 integrin was obtained using homology modeling based on the crystal coordinates of avb3 in its bound conformation as template. The modeled receptor was refined using energy minimization and molecular dynamics simulations in explicit solvent. The refined avb5 model was used to explore the interactions between this integrin and avb3/ avb5 dual and avb3-selective ligands in the attempt to provide a preliminary rationalization, at the molecular level, of ligand selectivity toward the two Rv integrins. It was found that, in the RGD binding site of the avb5 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 Rv integrins subtype ligand binding selectivity, in line with both mutagenesis data and SARs studies.
Human integrin αvβ5: homology modeling and ligand binding / Marinelli, Luciana; Gottschalk, K. E.; Meyer, A; Novellino, Ettore; Kessler, H.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 47:(2004), pp. 4166-4177. [10.1021/jm030635j]
Human integrin αvβ5: homology modeling and ligand binding.
MARINELLI, LUCIANA;NOVELLINO, ETTORE;
2004
Abstract
The recently reported crystal structures of the extracellular domains of the avb3 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 threedimensional model for the human avb5 integrin was obtained using homology modeling based on the crystal coordinates of avb3 in its bound conformation as template. The modeled receptor was refined using energy minimization and molecular dynamics simulations in explicit solvent. The refined avb5 model was used to explore the interactions between this integrin and avb3/ avb5 dual and avb3-selective ligands in the attempt to provide a preliminary rationalization, at the molecular level, of ligand selectivity toward the two Rv integrins. It was found that, in the RGD binding site of the avb5 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 Rv integrins subtype ligand binding selectivity, in line with both mutagenesis data and SARs studies.File | Dimensione | Formato | |
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