Open AccessPeptide mimetics of the thrombin-bound structure of fibrinopeptide A.
Author(s) -
Hiroshi Nakanishi,
R. A. Chrusciel,
Richard Shen,
Stephen R. Bertenshaw,
Michael E. Johnson,
T.J. Rydel,
A. Tulinsky,
Michaël Kahn
Publication year - 1992
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.89.5.1705
Subject(s) - thrombin , trypsin , peptide , chemistry , turn (biochemistry) , stereochemistry , protein structure , biophysics , nuclear overhauser effect , biochemistry , nuclear magnetic resonance spectroscopy , biology , enzyme , platelet , immunology
Recent work has suggested that the thrombin-bound conformation of fibrinopeptide A exhibits a strand-turn-strand motif, with a beta-turn centered at residues Glu-11 and Gly-12. Our molecular modeling analysis indicates that the published fibrinopeptide conformation cannot bind reasonably to thrombin but that reorientation of two residues by alignment with bovine pancreatic trypsin inhibitor provides a good fit within the deep thrombin cleft and satisfies all of the experimental nuclear Overhauser effect data. Based on this analysis, we have successfully designed and synthesized hybrid peptide mimetic substrates and inhibitors that mimic the proposed beta-turn structure. The results indicate that the turn conformation is an important aspect of thrombin specificity and that our turn mimetic design successfully mimics the thrombin-bound conformation of fibrinopeptide.