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Crystal Structure of the Complex Between Thrombin and the Central "E" Region of Fibrin

Published

Author(s)

I Pechik, J Madrazo, M W. Mosesson, I Hernandez, G L. Gilliland, L Medved

Abstract

Non-substrate interactions of thrombin with fibrin play an important role in modulating its procoagulant activity. To establish the structural basis for these interactions, we crystallized PPACK-inhibited thrombin in complex with a fragment, Eht , corresponding to the central region of fibrin, and solved its structure at 3.65 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 complimentary negatively charged surface of Eht. Among residues constituting the interface, Phe34, Ser36A, Leu65, Tyr76, Arg77A, Ile82 and Lys110 of thrombin and the A chain Trp33, Phe35, Asp38, Glu39, the B chain Ala68 and Asp69, and the chain Asp27 and Ser30 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.
Citation
Proceedings of the National Academy of Sciences of the United States of America
Volume
101
Issue
9

Keywords

fibrin, protein-protein interactions, structural biology, thrombin, thrombin-fibrin interactions, x-ray crystal structure

Citation

Pechik, I. , Madrazo, J. , Mosesson, M. , Hernandez, I. , Gilliland, G. and Medved, L. (2004), Crystal Structure of the Complex Between Thrombin and the Central "E" Region of Fibrin, Proceedings of the National Academy of Sciences of the United States of America (Accessed July 19, 2024)

Issues

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Created March 1, 2004, Updated October 12, 2021