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1. Introduction
2. Blood hemostasis
3. Activation of procoagulant factors by injury
4. Anticoagulant factors
5. The role of antithrombin and heparan sulfate
6. Antithrombin
7. Inherited deficiencies of antithrombin
8. Mutations causing antithrombin dysfunction
9. Serpins: proteolytic enzymes regulators
10. Serpins characteristics
11. Lock-and-key vs.serpin type protease inhibitors
12. Serpin type protease inhibitors structure
13. Inhibition mechanism through antithrombin activity
14. Heparin/heparan sulfate structure
15. Activation of antithrombin
16. X-ray structure of the antithrombin-heparin complex
17. Close-up of the heparin binding site of antithrombin
18. Antithrombin "hotspots" binding heparin
19. Heparin binds antithrombin in a two-step process
20. Antithrombin hotspots contribute to heparin binding
21. Effect of saccharides: antithrombin-heparin affinity
22. The induced-conformational change binding
23. Pre-equilibrium binding mechanism
24. Allosteric activation of antithrombin by heparin
25. Effect of heparin on antithrombin reactivity
26. Activation mechanisms of antithrombin by heparin
27. The bridging mechanism
28. The conformational activation mechanism (1)
29. The conformational activation mechanism (2)
30. Hypothesis: reactivity enhancment by reactive loop
31. Results of the hypothesis tested
32. Modified conformational activation mechanism
33. Mapping the antithrombin exosite (1)
34. Mapping the antithrombin exosite (2)
35. Localization of the exosite of antithrombin
36. Two residues mutants affect antithrombin reactivity
37. Antithrombin/heparin/FXa complexes structures
38. Heparin activation of antithrombin: summary
39. Conserved residues in the reactive loop sequences
40. Limited reactivity of serpin by the AT reactive loop
41. Molecular basis for antithrombin selective reactivity
42. Negative features of heparin anticoagulant thepray
43. Reference (1)
44. Reference (2)
45. Reference (3)

Topics Covered

• Antithrombin and hemostasis
• Dysfunctional antithrombins and thrombophilia
• Protease regulation by serpins
• Heparin requirement for antithrombin function
• Structural determinants of heparin binding to antithrombin
• Heparin-induced conformational changes in antithrombin
• Heparin as an allosteric activator of antithrombin
• Bridging and conformational change mechanisms of heparin activation of antithrombin
• Structural basis of conformational activation
• Role of exosites in conformational activation
• Role of the reactive loop in antithrombin anticoagulant function
• Implications for improved heparin anticoagulants

Links

Series:

• Protein Epidemiology

Categories:

• Biochemistry
• Cell Biology
• Clinical Practice

Therapeutic Areas:

• Haematology

Talk Citation

Olson, S. (2007, October 1). Regulation of blood coagulation by the serpin, antithrombin [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 26, 2024, from https://doi.org/10.69645/VLVT7240.
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Publication History

• Published on October 1, 2007
• Archived on April 27, 2016

Financial Disclosures

• Prof. Steve Olson has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.