Related Experiment Videos
Crystal structure of thrombin bound to heparin
Wendy J Carter1, Evis Cama, James A Huntington
1University of Cambridge, Department of Haematology, Division of Structural Medicine, Thrombosis Research Unit, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom.
The Journal of Biological Chemistry
|November 19, 2004
Summary
This study reveals the molecular details of how heparin interacts with thrombin, a key protein in blood clotting. Understanding this interaction is crucial for controlling bleeding and preventing thrombosis.
Area of Science:
- Biochemistry
- Structural Biology
- Hematology
Background:
- Thrombin, a protease in blood coagulation, has both pro- and anticoagulant functions.
- Substrate recognition by thrombin involves interactions outside its active site, mediated by anion binding exosites.
- Glycosaminoglycan binding to exosite II is critical for inhibiting thrombin's procoagulant activity.
Purpose of the Study:
- To elucidate the molecular interactions between thrombin and heparin at atomic resolution.
- To provide a detailed structural basis for heparin's role in regulating thrombin activity.
Main Methods:
- X-ray crystallography of human alpha-thrombin bound to an eight-monosaccharide heparin fragment.
- Analysis of the 1.85-Å resolution structure.
Main Results:
- The structure reveals two thrombin dimers, each associated with a single heparin octasaccharide.
- Detailed molecular interactions between heparin and thrombin exosite II were observed.
- These interactions are consistent with previous mutagenesis data.
Conclusions:
- The structure provides a molecular understanding of heparin-thrombin interactions at exosite II.
- This interaction is critical for regulating thrombin's procoagulant functions and localizing clotting.
- The findings support the role of exosite II in mediating thrombin's inhibition and localization.