The present study deals with the conformation in solution of two heparin octasaccharides containing the pentasaccharide sequence GlcNNAc,6S-GlcA-GlcNNS,3,6S-IdoA2S-GlcNNS,6S [AGA*IA; where GlcNNAc,6S is N-acetylated, 6-O-sulfated α-D-glucosamine, GlcNNS,3,6S is N,3,6-O-trisulfated α-D-glucosamine and IdoA2S is 2-O-sulfated IdoA (α-L-iduronic acid)] located at different positions in the heparin chain and focuses on establishing geometries of IdoA residues (IdoA2S and IdoA) both inside and outside the AGA*IA sequence. AGA*IA constitutes the active site for AT (antithrombin) and is essential for the expression of high anticoagulant and antithrombotic activities. Analysis of NMR parameters [NOEs (nuclear Overhauser effects), transferred NOEs and coupling constants] for the two octasaccharides indicated that between the 1C4 and 2S0 conformations present in dynamic equilibrium in the free state for the IdoA2S residue within AGA*IA, AT selects the 2S0 form, as previously shown [Hricovini, Guerrini, Bisio, Torri, Petitou and Casu (2001) Biochem. J. 359, 265–272]. Notably, the 2S0 conformation is also adopted by the non-sulfated IdoA residue preceding AGA*IA that, in the absence of AT, adopts predominantly the 1C4 form. These results further support the concept that heparin-binding proteins influence the conformational equilibrium of iduronic acid residues that are directly or indirectly involved in binding and select one of their equi-energetic conformations for best fitting in the complex. The complete reversal of an iduronic acid conformation preferred in the free state is also demonstrated for the first time. Preliminary docking studies provided information on the octasaccharide binding location agreeing most closely with the experimental data. These results suggest a possible biological role for the non-sulfated IdoA residue preceding AGA*IA, previously thought not to influence the AT-binding properties of the pentasaccharide. Thus, for each AT binding sequence longer than AGA*IA, the interactions with the protein could differ and give to each heparin fragment a specific biological response.
Skip Nav Destination
Article navigation
October 2006
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
September 27 2006
Conformational transitions induced in heparin octasaccharides by binding with antithrombin III
Marco Guerrini;
Marco Guerrini
1
*‘G. Ronzoni’ Institute for Chemical and Biochemical Research, via G. Colombo 81, 20133 Milan, Italy
1To whom correspondence should be addressed (email guerrini@ronzoni.it).
Search for other works by this author on:
Sara Guglieri;
Sara Guglieri
*‘G. Ronzoni’ Institute for Chemical and Biochemical Research, via G. Colombo 81, 20133 Milan, Italy
Search for other works by this author on:
Daniela Beccati;
Daniela Beccati
*‘G. Ronzoni’ Institute for Chemical and Biochemical Research, via G. Colombo 81, 20133 Milan, Italy
Search for other works by this author on:
Giangiacomo Torri;
Giangiacomo Torri
*‘G. Ronzoni’ Institute for Chemical and Biochemical Research, via G. Colombo 81, 20133 Milan, Italy
Search for other works by this author on:
Christian Viskov;
Christian Viskov
†Sanofi-Aventis, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France
Search for other works by this author on:
Pierre Mourier
Pierre Mourier
†Sanofi-Aventis, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
May 03 2006
Revision Received:
June 07 2006
Accepted:
June 23 2006
Accepted Manuscript online:
June 23 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 399 (2): 191–198.
Article history
Received:
May 03 2006
Revision Received:
June 07 2006
Accepted:
June 23 2006
Accepted Manuscript online:
June 23 2006
Citation
Marco Guerrini, Sara Guglieri, Daniela Beccati, Giangiacomo Torri, Christian Viskov, Pierre Mourier; Conformational transitions induced in heparin octasaccharides by binding with antithrombin III. Biochem J 15 October 2006; 399 (2): 191–198. doi: https://doi.org/10.1042/BJ20060656
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.