The interaction, in aqueous solution, of the synthetic pentasaccharide AGA∗IAM (GlcN,6-SO3α1–4GlcAβ1–4GlcN,3,6-SO3α1–4IdoA,2-SO3α1–4GlcN,6-SO3αOMe; where GlcN,6-SO3 is 2-deoxy-2-sulphamino-α-d-glucopyranosyl 6-sulphate, IdoA is l-iduronic acid and IdoA2-SO3 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–AM (where G, I, A and AM are β-d-glucuronic acid, 2-O-sulphated α-l-iduronic acid, N,6-O-sulphated α-d-glucosamine and the α-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 2S0 form.
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October 2001
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Research Article|
October 08 2001
Conformation of heparin pentasaccharide bound to antithrombin III
Miloš HRICOVÍNI;
Miloš HRICOVÍNI
1
∗Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, 842 38 Bratislava, Slovakia
1To whom correspondence should be addressed (e-mail hricovini@savba.sk).
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Marco GUERRINI;
Marco GUERRINI
†“G. Ronzoni” Institute for Chemical and Biochemical Research, G. Colombo 81, 201 33 Milan, Italy
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Antonella BISIO;
Antonella BISIO
†“G. Ronzoni” Institute for Chemical and Biochemical Research, G. Colombo 81, 201 33 Milan, Italy
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Giangiacomo TORRI;
Giangiacomo TORRI
†“G. Ronzoni” Institute for Chemical and Biochemical Research, G. Colombo 81, 201 33 Milan, Italy
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Maurice PETITOU;
Maurice PETITOU
‡Sanofi Recherche, 195 Route d'Espagne, B. P. 1169-31036, Toulouse, France
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Benito CASU
Benito CASU
†“G. Ronzoni” Institute for Chemical and Biochemical Research, G. Colombo 81, 201 33 Milan, Italy
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Publisher: Portland Press Ltd
Received:
May 21 2001
Revision Received:
June 25 2001
Accepted:
August 08 2001
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2001
2001
Biochem J (2001) 359 (2): 265–272.
Article history
Received:
May 21 2001
Revision Received:
June 25 2001
Accepted:
August 08 2001
Citation
Miloš HRICOVÍNI, Marco GUERRINI, Antonella BISIO, Giangiacomo TORRI, Maurice PETITOU, Benito CASU; Conformation of heparin pentasaccharide bound to antithrombin III. Biochem J 15 October 2001; 359 (2): 265–272. doi: https://doi.org/10.1042/bj3590265
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