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      Residues Tyr253and Glu255in Strand 3 of β-Sheet C of Antithrombin Are Key Determinants of an Exosite Made Accessible by Heparin Activation to Promote Rapid Inhibition of Factors Xa and IXa

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      Journal of Biological Chemistry

      American Society for Biochemistry & Molecular Biology (ASBMB)

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          Most cited references 34

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          Cation-pi interactions in structural biology.

          Cation-pi interactions in protein structures are identified and evaluated by using an energy-based criterion for selecting significant sidechain pairs. Cation-pi interactions are found to be common among structures in the Protein Data Bank, and it is clearly demonstrated that, when a cationic sidechain (Lys or Arg) is near an aromatic sidechain (Phe, Tyr, or Trp), the geometry is biased toward one that would experience a favorable cation-pi interaction. The sidechain of Arg is more likely than that of Lys to be in a cation-pi interaction. Among the aromatics, a strong bias toward Trp is clear, such that over one-fourth of all tryptophans in the data bank experience an energetically significant cation-pi interaction.
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            The anticoagulant activation of antithrombin by heparin.

            Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the coagulation proteases until it binds to the heparan side chains that line the microvasculature. The binding specifically occurs to a core pentasaccharide present both in the heparans and in their therapeutic derivative heparin. The accompanying conformational change of antithrombin is revealed in a 2.9-A structure of a dimer of latent and active antithrombins, each in complex with the high-affinity pentasaccharide. Inhibitory activation results from a shift in the main sheet of the molecule from a partially six-stranded to a five-stranded form, with extrusion of the reactive center loop to give a more exposed orientation. There is a tilting and elongation of helix D with the formation of a 2-turn helix P between the C and D helices. Concomitant conformational changes at the heparin binding site explain both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin-protease complex into the circulation. The pentasaccharide binds by hydrogen bonding of its sulfates and carboxylates to Arg-129 and Lys-125 in the D-helix, to Arg-46 and Arg-47 in the A-helix, to Lys-114 and Glu-113 in the P-helix, and to Lys-11 and Arg-13 in a cleft formed by the amino terminus. This clear definition of the binding site will provide a structural basis for developing heparin analogues that are more specific toward their intended target antithrombin and therefore less likely to exhibit side effects.
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              Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin.

              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 A 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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                Author and article information

                Journal
                Journal of Biological Chemistry
                J. Biol. Chem.
                American Society for Biochemistry & Molecular Biology (ASBMB)
                0021-9258
                1083-351X
                May 05 2006
                May 12 2006
                May 12 2006
                March 03 2006
                : 281
                : 19
                : 13424-13432
                Article
                10.1074/jbc.M600415200
                © 2006
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