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Interaction of thrombin with sucrose octasulfate
Bijoy J Desai1, Rio S Boothello, Akul Y Mehta
1Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23219, United States.
Biochemistry
|July 9, 2011
Summary
Sucrose octasulfate (SOS) mimics heparin’s binding to thrombin, inhibiting its activity. However, SOS binding differs structurally and chemically, offering new avenues for designing small molecule thrombin modulators.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Thrombin, a serine protease, is crucial in coagulation, acting as both a pro- and anticoagulant.
- Heparin, a glycosaminoglycan, modulates thrombin activity via exosite II binding.
- Sucrose octasulfate (SOS) is a potential heparin surrogate, but its interaction with thrombin is not fully understood.
Purpose of the Study:
- To characterize the interaction between sucrose octasulfate (SOS) and thrombin.
- To determine the crystal structure of the SOS-thrombin complex.
- To compare SOS and heparin binding to thrombin and their effects on thrombin activity.
Main Methods:
- Solution-based binding assays (K(d) determination).
- Analytical ultracentrifugation to assess thrombin aggregation state.
- X-ray crystallography to elucidate complex structure.
Main Results:
- SOS binds thrombin with a K(d) of ~1.4 microM, comparable to heparin.
- Nonionic interactions contribute more to SOS binding than heparin.
- SOS binding inhibits thrombin activity with high potency but low efficacy.
- SOS binding prevents thrombin dimerization, unlike heparin.
- Crystal structure reveals distinct binding modes of SOS and heparin at exosite II.
Conclusions:
- SOS is a functional heparin mimic for thrombin binding but exhibits significant differences in chemical and structural interactions.
- These distinctions, particularly in thrombin inhibition and aggregation state, provide insights for designing novel allosteric small molecule modulators targeting thrombin's exosite II.
