Premium
Conformational Selection of the AGA*IA M Heparin Pentasaccharide when Bound to the Fibroblast Growth Factor Receptor
Author(s) -
Nieto Lidia,
Canales Ángeles,
GiménezGallego Guillermo,
Nieto Pedro M.,
JiménezBarbero Jesús
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201101000
Subject(s) - chemistry , residue (chemistry) , stereochemistry , conformational isomerism , conformational change , ligand (biochemistry) , receptor , biochemistry , molecule , organic chemistry
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.