The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity

Nature Structural and Molecular Biology

Volumn 11, Issue 9, 2004, Pages 863-867

  Dementiev, Alexey ^a   Petitou, Maurice ^b   Herbert, Jean Marc ^b   Gettins, Peter G W ^a  

^a UNIVERSITY OF ILLINOIS   (United States)

^b SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANHYDROTHROMBIN; ANTITHROMBIN; HEPARIN; OLIGOSACCHARIDE; PENTASACCHARIDE; PROTEINASE; SERINE PROTEINASE INHIBITOR; SR 123781A; THROMBIN; THROMBIN ANTITHROMBIN COMPLEX; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; BINDING SITE; BLOOD CLOTTING; CRYSTAL STRUCTURE; ENZYME INHIBITOR COMPLEX; MUTAGENESIS; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN PROTEIN INTERACTION;

ANTITHROMBINS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; FIBRINOLYTIC AGENTS; GLYCOSAMINOGLYCANS; HEPARIN; HUMANS; MODELS, CHEMICAL; MODELS, MOLECULAR; OLIGOSACCHARIDES; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN STRUCTURE, TERTIARY; PROTEINS; THROMBIN;

EID: 4344710558     PISSN: 15459993     EISSN: None     Source Type: Journal    
DOI: 10.1038/nsmb810     Document Type: Article

References (40)

1. Olson, S.T. & Björk, I. Mechanism of action of heparin and heparin-like antithrombotics. Persp. Drug Discovery Design 1, 479-501 (1994).
2. Levine, M.N. & Hirsh, J. Clinical use of low molecular weight heparins and heparinoids. Sem. Thromb. Hemost. 14, 116-125 (1988).
3. Gettins, P.G.W. Serpin structure, mechanism and function. Chem. Rev. 102, 4751-4804 (2002).
4. Desai, U., Petitou, M., Björk, I. & Olson, S.T. Mechanism of heparin activation of antithrombin. Role of individual residues of the pentasaccharide in the recognition of native and activated states of antithrombin. J. Biol. Chem. 273, 7478-7487 (1998).
5. Desai, U., Petitou, M., Björk, I. & Olson, S.T. Mechanism of heparin activation of antithrombin. Evidence for an induced-fit model of allosteric activation involving two interaction subsites. Biochemistry 37, 13033-13041 (1998).
6. Huntington, J.A., Olson, S.T., Fan, B. & Gettins, P.G.W. Mechanism of heparin activation of antithrombin. Evidence for reactive center loop pre-insertion with expulsion upon heparin binding. Biochemistry 35, 8495-8503 (1996).
7. Olson, S.T. & Björk, I. Predominant contribution of surface approximation to the mechanism of heparin acceleration of the antithrombin-thrombin reaction. Elucidation from salt concentration effects. J. Biol. Chem. 266, 6353-6364 (1991).
8. Herbert, J.M. et al. SR123781A, a synthetic heparin mimetic. Thromb. Haemost. 85, 852-860 (2001).
9. Petitou, M. et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 398, 417-422 (1999).
10. Grootenhuis, P.D.J., Westerduin, P., Meuleman, D., Petitou, M. & van Boeckel, C.A. Rational design of synthetic heparin analogues with tailor-made coagulation inhibitory activity. Nat. Struct. Biol. 2, 736-739 (1995).
11. Olson, S.T., Halvorson, H.R. & Björk, I. Quantitative characterization of the thrombin-heparin interaction. Discrimination between specific and nonspecific binding models. J. Biol. Chem. 266, 6342-6352 (1991).
12. Jin, L. et al. The anticoagulant activation of antithrombin by heparin. Proc. Natl. Acad. Sci. USA 94, 14683-14688 (1997).
13. Baglin, T.P., Carrell, R.W., Church, F.C., Esmon, C.T. & Huntington, J.A. Crystal structure of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc. Natl. Acad. Sci. USA 99, 11079-11084 (2002).
14. Skinner, R. et al. The 2.6Å structure of antithrombin indicates a conformational change at the heparin binding site. J. Mol. Biol. 266, 601-609 (1997).
15. Ye, S. et al. The structure of a Michaelis serpin-protease complex. Nature Struct. Biol. 8, 979-983 (2001).
16. Dementiev, A., Simonovic, M., Volz, K. & Gettins, P.G.W. Canonical inhibitor-like interactions explain reactivity of arproteinase inhibitor Pittsburgh and antithrombin with proteinases. J. Biol. Chem. 278, 37881-37887 (2003).
17. Rezaie, A.R. Role of Leu99 of thrombin in determining the P2 specificity of serpins. Biochemistry 36, 7437-7446 (1997).
18. Chuang, Y.-J., Gettins, P.G.W. & Olson, S.T. Importance of the P2 glycine of antithrombin in target proteinase specificity, heparin activation and the efficiency of proteinase trapping as revealed by a P2 Gly→Pro mutation. J. Biol. Chem. 274, 28142-28149 (1999).
19. Carrell, R.W. Stein, P.E., Fermi, G. & Wardell, M.R. Biological implications of a 3Å structure of dimeric antithrombin. Structure 2, 257-270 (1994).
20. Skinner, R. et al. Implications for function and therapy of a 2.9Å structure of binary-complexed antithrombin. J. Mol. Biol. 283, 9-14 (1998).
21. Huntington, J.A. McCoy, A., Pei, X., Gettins, P.G.W. & Carrell, R.W. 2.85Å structure of antithrombin variant S380C-fluorescein reveals the trigger for allosteric activation. J. Biol. Chem. 275, 15377-15383 (1999).
22. Schreuder, H.A. et al. The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions. Nat. Struct. Biol. 1, 48-54 (1994).
23. 13C nuclear magnetic resonance studies. Biochem. J. 197, 599-609 (1981).
24. Choay, J. et al. Structure-activity relationship in heparin: asynthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem. Biophys. Res. Commun. 116, 492-499 (1983).
25. Laurent, T.C., Tengblad, A., Thunberg, L., Höök, M. & Lindahl, U. The molecular weight dependence of the anti-coagulant activity of heparin. Biochem. J. 175, 691-701 (1978).
26. Sheehan, J.P. & Sadler, J.E. Molecular mapping of the heparin-binding exosite of thrombin. Proc. Natl. Acad. Sci. USA 91, 5518-5522 (1994).
27. Petitou, M., Lormeau, J.-C. & Choay, J. Chemical synthesis of glycosaminoglycans: New approaches to antithrombic drugs. Nature 350 (suppl.), 30-33 (1991).
28. Li, W., Johnson, D.J.D., Esmon, C.T. & Huntington, J.A. 2.5Å structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat. Struct. Mol. Biol. 11, advance online publication, 15 August 2004(doi:10.1038/nsmb811).
29. Rezaie, A.R. Reactivities of the S2 and S3 subsite residues of thrombin with the native and heparin-induced conformers of antithrombin. Protein Sci. 7, 349-357 (1998).
30. Rezaie, A.R. & Olson, S.T. Contribution of lysine 60f to S1′ specificity of thrombin. Biochemistry 36, 1026-1033 (1997).
31. Rezaie, A.R. Tryptophan 60-D in the B-insertion loop of thrombin modulated the thrombin-antithrombin reaction. Biochemistry 35, 1918-1924 (1996).
32. 3′ subsites of thrombin. J. Biol. Chem. 275, 809-816 (2000).
33. Bode, W., Turk, D. & Karshikov, A. The refined 1.9Å X-ray crystal structure of D-Phe-Pro-Arg-chloromethylketone-inhibited human α-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci. 1, 426-471 (1992).
34. He, X.H., Ye, J., Esmon, C.T. & Rezaie, A.R. Influence of arginines 93, 97, and 101 of thrombin to its functional specificity. Biochemistry 36, 8969-8976 (1997).
35. Meagher, J.L., Huntington, J.A., Fan, B. & Gettins, P.G.W. Role of arginine 132 and lysine 133 in heparin binding to, and activation of, antithrombin. J. Biol. Chem. 271, 29353-29358 (1996).
36. Ngai, P.K. & Chang, J.-Y. A novel one-step purification of human α-thrombin after direct activation of crude prothrombin enriched from plasma. Biochem. J. 280, 805-808 (1991).
37. Ashton, R.W. & Scheraga, H.A. Preparation and characterization of anhydrothrombin. Biochemistry 34, 6454-6463 (1995).
38. Otwinowski, Z. & Minor, W. Processing of x-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 461-472 (1997).
39. Brünger, A.T. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905-921 (1998).
40. Choay, J., Lormeau, J.-C. & Petitou, M. Low molecular weight oligosaccharides active in plasma against factor Xa. Ann. Pharm. Fr. 39, 37-44 (1981).