Nature Structural & Molecular Biology11, 863 - 867 (2004)
Published online: 15 August 2004; | doi:10.1038/nsmb810
The ternary complex of antithrombin−anhydrothrombin−heparin reveals the basis of inhibitor specificity
Alexey Dementiev1, Maurice Petitou2, Jean-Marc Herbert2
& Peter G W Gettins1
1
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, 900 S. Ashland, Chicago, Illinois 60607, USA.
2
Sanofi-Synthélabo, 185 Route d'Espagne, 31036 Toulouse Cedex, France.
Correspondence should be addressed to Peter G W Gettins pgettins@uic.edu
Antithrombin, the principal physiological inhibitor of the blood coagulation proteinase thrombin, requires heparin as a cofactor. We report the crystal structure of the rate-determining encounter complex formed between antithrombin, anhydrothrombin and an optimal synthetic 16-mer oligosaccharide. The antithrombin reactive center loop projects from the serpin body and adopts a canonical conformation that makes extensive backbone and side chain contacts from P5 to P6' with thrombin's restrictive specificity pockets, including residues in the 60-loop. These contacts rationalize many earlier mutagenesis studies on thrombin specificity. The 16-mer oligosaccharide is just long enough to form the predicted bridge between the high-affinity pentasaccharide-binding site on antithrombin and the highly basic exosite 2 on thrombin, validating the design strategy for this synthetic heparin. The protein-protein and protein-oligosaccharide interactions together explain the basis for heparin activation of antithrombin as a thrombin inhibitor.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
