title: Molecular model of the alpha(IIb)beta(3) integrin.
abstract: A molecular model of the alpha(IIb)beta(3) integrin has been developed utilizing (i). the crystal structure of alpha(v)beta(3), (ii). homology model of the alpha(IIb) subdomain, and (iii). the docking of alpha(IIb)beta(3)/alpha(v)beta(3) dual and selective inhibitors into the putative binding sites of alpha(IIb)beta(3) and alpha(v)beta(3). Since the binding sites of these integrins are located at the interface between the two heads of the individual subunits, only the alpha(IIb)beta(3) head region is modeled. The 3D conformations of two loops in alpha(IIb), whose residues have been implicated in non-peptide ligand binding, could not be determined from homology with alpha(v) 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 phi/psi angles and contribute to a binding site model of alpha(IIb)beta(3) that is consistent with both the known mutagenesis studies and in-house structure-activity relationships. The charged residues alpha(IIb):E117 and beta(3):R214 are found to dominate the ligand-protein binding interaction. The previously identified "exosite" is also identified as a hydrogen bond, hydrophobic or pi-pi interaction with Y190, similar to the recently proposed binding model of alpha(v)beta(3).
authors.affiliation: Departments of Molecular Systems and Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. bradley_feuston@merck.com
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Feuston
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Culberson
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D008024:Ligands; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011725:Pyridines; D013449:Sulfonamides