Heparin and heparin-like oligo- and polysaccharides bind to fibroblast growth factors (FGFs) and modulate their ability to form active ternary complexes with FGF receptors (FGFRs). Considerable efforts have been made in recent years to identify the minimal heparin and heparan sulfate (HS) sequences that bind and activate individual FGFs. Heparin sequences involved in interaction with FGFs invariably contain at least one residue of 2-O-sulfated iduronic acid (IdoA2S), which adopts either the 1C4 chair conformation or the equienergetic skew-boat 2S0. In solution and in the absence of a binding protein, both these conformations are present in a dynamic equilibrium. In oligosaccharide-protein co-crystals, the protein selects those conformers that provide optimal contacts. The crystalline structure of a heparin hexasaccharide/FGF complex exhibits one of the two IdoA2S residues in the active site of the growth factor in 1C4 conformation and the other (outside the active site) in 2S0 conformation. NMR studies suggest that active conformations of heparin/HS oligosaccharides in solution could be distinct from those adopted in crystals. Heparin tetrasaccharides in the presence of FGF1 and FGF2 have both their IdoA2S residues prevalently in the 1C4 form. Current NMR and molecular modelling studies are being extended to longer heparin oligosaccharides as well as to heparins with “glycol-split” residues along their chains.
Keywords: heparin, FGF, oligosaccharide conformation, protein-carbohydrate interaction, NMR spectroscopy
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