title: A 3D structure model of integrin alpha 4 beta 1 complex: I. Construction of a homology model of beta 1 and ligand binding analysis.
abstract: It is well established that integrin alpha 4 beta 1 binds to the vascular cell adhesion molecule (VCAM) and fibronectin and plays an important role in signal transduction. Blocking the binding of VCAM to alpha 4 beta 1 is thought to be a way of controlling a number of disease processes. To better understand how various inhibitors might block the interaction of VCAM and fibronectin with alpha 4 beta 1, we began constructing a structure model for the integrin alpha 4 beta 1 complex. As the first step, we have built a homology model of the beta 1 subunit based on the I domain of the integrin CD11B subunit. The model, including a bound Mg(2+) ion, was optimized through a specially designed relaxation scheme involving restrained minimization and dynamics steps. The native ligand VCAM and two highly active small molecules (TBC772 and TBC3486) shown to inhibit binding of CS-1 and VCAM to alpha 4 beta 1 were docked into the active site of the refined model. Results from the binding analysis fit well with a pharmacophore model that was independently derived from active analog studies. A critical examination of residues in the binding site and analysis of docked ligands that are both potent and selective led to the proposal of a mechanism for beta 1/beta 7 ligand binding selectivity.
authors.affiliation: Department of Medicinal Chemistry and Biophysics, Texas Biotechnology Corporation, Houston, Texas 77030, USA. tyou@tbc.com
authors.forename: Tony J
authors.initials: TJ
authors.lastname: You
authors.forename: David S
authors.initials: DS
authors.lastname: Maxwell
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kogan
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Jamal
authors.initials: J
authors.lastname: Kassir
authors.forename: George W
authors.initials: GW
authors.lastname: Holland
authors.forename: Richard A F
authors.initials: RA
authors.lastname: Dixon
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005353:Fibronectins / Q000378:metabolism; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000737:chemistry; D016023:Integrins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D021122:Protein Subunits; D016201:Receptors, Lymphocyte Homing / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013816:Thermodynamics; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D005353:Fibronectins; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D008024:Ligands; D021122:Protein Subunits; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1