title: Conformational selection of the AGA*IA(M) heparin pentasaccharide when bound to the fibroblast growth factor receptor.
abstract: The interaction of the synthetic pentasaccharide AGA*IA(M) (GlcNS,6S-GlcA-GlcNS,3S,6S-IdoA2S-GlcNS,6S-Me) with the extracellular Ig2 domain of the fibroblast growth factor receptor (FGFR2) has been studied by NMR and computational methods. Analysis of the heparin pentasaccharide in the free state and in the complex indicates the existence of a conformational selection process. Although an equilibrium exists between the (1)C(4) and (2)S(0) conformers (ratio 60:40) of the 2-O-sulfo-α-L-iduronate ring (IdoA2S) in the free state, FGFR2 selects only the unique twisted-boat (2)S(0) conformation of this IdoA2S residue. In addition, the protein residues involved in the binding with AGA*IA(M) have also been characterized. The NMR results obtained, from both the ligand and protein perspective, were employed to model the bound conformation of the pentasaccharide by a combined docking and molecular dynamic simulation approach.
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Nieto
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Canales
authors.forename: Guillermo
authors.initials: G
authors.lastname: Giménez-Gallego
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Nieto
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
mesh_terms: D000990:Antithrombin III / Q000737:chemistry* / Q000378:metabolism; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D007067:Iduronic Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism
chemical_list: D009844:Oligosaccharides; D017468:Receptors, Fibroblast Growth Factor; D007067:Iduronic Acid; D000990:Antithrombin III; D006493:Heparin