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Structure of the antithrombin–thrombin–heparin ternary complex reveals the antithrombotic mechanism of heparin

Abstract

The maintenance of normal blood flow depends completely on the inhibition of thrombin by antithrombin, a member of the serpin family. Antithrombin circulates at a high concentration, but only becomes capable of efficient thrombin inhibition on interaction with heparin or related glycosaminoglycans. The anticoagulant properties of therapeutic heparin are mediated by its interaction with antithrombin, although the structural basis for this interaction is unclear. Here we present the crystal structure at a resolution of 2.5 Å of the ternary complex between antithrombin, thrombin and a heparin mimetic (SR123781). The structure reveals a template mechanism with antithrombin and thrombin bound to the same heparin chain. A notably close contact interface, comprised of extensive active site and exosite interactions, explains, in molecular detail, the basis of the antithrombotic properties of therapeutic heparin.

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Figure 1: Heparin catalysis of thrombin inhibition by antithrombin.
Figure 2: Extensive interactions between the RCL of antithrombin and the active site of thrombin.
Figure 3: Thrombin exosite interactions.

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Acknowledgements

The authors are grateful to M. Petitou of Sanofi Synthelabo for providing the heparin mimetic SR123781 for crystallization, and to R. Carrell for comments on the manuscript. Funding for J.A.H. was provided by the NIH (R01 HL68629) and the Medical Research Council (UK), and C.T.E. is a Howard Hughes Investigator.

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Correspondence to James A Huntington.

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Li, W., Johnson, D., Esmon, C. et al. Structure of the antithrombin–thrombin–heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol 11, 857–862 (2004). https://doi.org/10.1038/nsmb811

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