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Enhancement of Thrombin Receptor Activation by Thrombin Receptor-Derived Heptapeptide with para-Fluorophenylalanine in Place of Phenylalanine

https://doi.org/10.1006/bbrc.1993.1680Get rights and content

Abstract

Thrombin receptor-derived peptide SFLLRNP (one-letter amino acid code) which corresponds to the N-terminal heptapeptide of tethered ligand is able to activate thrombin receptor and to stimulate the phosphoinositide (PI) turnover. The replacement of Phe-2 by Ala eliminated this activity completely, showing the crucial role of the Phe-phenyl group in receptor activation. It was found that substitution of para-fluorophenylalanine ((p-F)Phe) for Phe-2 enhanced several times the PI-turnover activity of SFLLRNP. This is the first example to date of a substitution with one order of magnitude greater increase in receptor activation. The Phe-2/Tyr substitution diminished the activity drasticaliy (almost 2% of SFLLRNP), indicating the importance of hydrophobicity of Phe2-phenyl. The Phe-2/Leu substitution, however, diminished also the activity (less than 2% of SFLLRNP). These results suggested that highly specific hydrophobic interaction exists between Phe-2 of the tethered ligand and its binding site in thrombin receptor.

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    As mentioned above, this enhancing effect most strongly affects the benzene CH atoms on the ortho position, but also weakly affects those on the meta and para positions. Such an enhancing effect was observed notably for S/(4-F1)Phe/LLRNP (Fig. 8A), which exhibited the highest activity (250%) among (Fn)Phe-containing homologs.22 Similar notable effects were also observed for S/(2,4,6-F3)Phe/LLRNP (49%), which was approximately four times more potent than S/(2,6-F2)Phe/LLRNP (11%) (Fig. 8B).

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