Crystal structure of the complex between thrombin and the central “E” region of fibrin

AUTOR(ES)

Pechik, Igor

FONTE

National Academy of Sciences

RESUMO

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, Eht, corresponding to the central region of human fibrin, and solved its structure at 3.65-Å resolution. The structure revealed that the complex consists of two thrombin molecules bound to opposite sides of the central part of Eht 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 Eht. Among residues constituting the interface, Phe-34, Ser-36A, Leu-65, Tyr-76, Arg-77A, Ile-82, and Lys-110 of thrombin and the Aα chain Trp-33, Phe-35, Asp-38, Glu-39, the Bβ chain Ala-68 and Asp-69, and the γ chain Asp-27 and Ser-30 of Eht 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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