Conformation of heparin pentasaccharide bound to antithrombin III

The interaction, in aqueous solution, of the synthetic pentasaccharide AGA*IA(M) (GlcN,6-SO(3)alpha 1-4GlcA beta 1-4GlcN,3,6-SO(3)alpha 1-4IdoA,2-SO(3)alpha 1-4GlcN,6-SO(3)alpha OMe; where GlcN,6-SO(3) is 2-deoxy-2-sulphamino-alpha-D-glucopyranosyl 6-sulphate, IdoA is l-iduronic acid and IdoA2-SO(3)...

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Bibliographic Details
Published in:Biochemical journal 2001-10, Vol.359 (Pt 2), p.265-272
Main Authors: Hricovíni, M, Guerrini, M, Bisio, A, Torri, G, Petitou, M, Casu, B
Format: Article
Language:English
Subjects:
Antithrombin III - chemistry
Antithrombin III - metabolism
Binding Sites
Carbohydrate Conformation
Carbohydrate Sequence
Heparin - chemistry
Heparin - metabolism
In Vitro Techniques
Macromolecular Substances
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Sequence Data
Oligosaccharides - chemistry
Oligosaccharides - metabolism
Protein Binding
Protein Conformation
Solutions
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Summary:The interaction, in aqueous solution, of the synthetic pentasaccharide AGA*IA(M) (GlcN,6-SO(3)alpha 1-4GlcA beta 1-4GlcN,3,6-SO(3)alpha 1-4IdoA,2-SO(3)alpha 1-4GlcN,6-SO(3)alpha OMe; where GlcN,6-SO(3) is 2-deoxy-2-sulphamino-alpha-D-glucopyranosyl 6-sulphate, IdoA is l-iduronic acid and IdoA2-SO(3) is L-iduronic acid 2-sulphate), which exactly reproduces the structure of the specific binding sequence of heparin and heparan sulphate for antithrombin III, has been studied by NMR. In the presence of antithrombin there were marked changes in the chemical shifts and nuclear Overhauser effects (NOEs), compared with the free state. On the basis of the optimized geometry of the pentasaccharide the transferred NOEs were interpreted with full relaxation and conformational exchange matrix analysis. An analysis of the three-dimensional structures of the pentasaccharide in the free state, and in the complex, revealed the binding to be accompanied by dihedral angle variation at the A-G and I-A(M) (where G, I, A and A(M) are beta-d-glucuronic acid, 2-O-sulphated alpha-L-iduronic acid, N,6-O-sulphated alpha-D-glucosamine and the alpha-methyl-glycoside of A respectively) glycosidic linkages. Evidence is also provided that the protein drives the conformation of the 2-O-sulphated iduronic acid residue towards the skewed (2)S(0) form.
ISSN:0264-6021
1470-8728
DOI:10.1042/0264-6021:3590265