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  • Title: Crystal structure of the complex between thrombin and the central "E" region of fibrin.
    Author: Pechik I, Madrazo J, Mosesson MW, Hernandez I, Gilliland GL, Medved L.
    Journal: Proc Natl Acad Sci U S A; 2004 Mar 02; 101(9):2718-23. PubMed ID: 14978285.
    Abstract:
    Nonsubstrate interactions of thrombin with fibrin play an important role in modulating its procoagulant activity. To establish the structural basis for these interactions, we crystallized d-Phe-Pro-Arg-chloromethyl ketone-inhibited human thrombin in complex with a fragment, E(ht), corresponding to the central region of human fibrin, and solved its structure at 3.65-A resolution. The structure revealed that the complex consists of two thrombin molecules bound to opposite sides of the central part of E(ht) in a way that seems to provide proper orientation of their catalytic triads for cleavage of fibrinogen fibrinopeptides. As expected, binding occurs through thrombin's anion-binding exosite I. However, only part of it is involved in forming an interface with the complementary negatively charged surface of E(ht). Among residues constituting the interface, Phe-34, Ser-36A, Leu-65, Tyr-76, Arg-77A, Ile-82, and Lys-110 of thrombin and the A alpha chain Trp-33, Phe-35, Asp-38, Glu-39, the B beta chain Ala-68 and Asp-69, and the gamma chain Asp-27 and Ser-30 of E(ht) form a net of polar contacts surrounding a well defined hydrophobic interior. Thus, despite the highly charged nature of the interacting surfaces, hydrophobic contacts make a substantial contribution to the interaction.
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