Edge-to-face CH/π interaction between ligand Phe-phenyl and receptor aromatic group in the thrombin receptor activation

A. Matsushima, T. Fujita, T. Nose, Y. Shimohigashi

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24 Citations (Scopus)

Abstract

In the ligand/receptor interaction, the side chain phenyl group of phenylalanine (Phe) is involved in a so-called hydrophobic interaction, in which the Phe-phenyl group functions as a π element or merely as a hydrophobic element. The thrombin receptor-tethered ligand SFLLRNP consists of the Phe-2 residue essential for receptor activation. In order to explore the molecular characteristics of this Phe-2-phenyl group, a complete set of S/Phe/LLRNP peptides comprising six different difluorophenylalanine isomers [(F2)Phe] was newly synthesized and assayed to evaluate their ability to induce the aggregation of human platelets. The assay results clarified several important structural elements to conclude that Phe-2-phenyl of S/Phe/LLRNP is in the edge-to-face CH/π interaction with the receptor aromatic group, utilizing the Phe-phenyl edge along with adjacent benzene hydrogens at positions (2-3) or (5-6). It was also found that the fluorine atom at position 4 increases the acidity of the hydrogen mainly at its ortho position, resulting in a reinforcement of the CH/π interaction and thus in an enhancement of biological activity. The H→F replacement in the benzene ring was found to provide an effective structural examination to the Phe residue; i.e., to identify the hydrogens in the CH/π interaction, and to strengthen the CH/π interaction.

Original languageEnglish
Pages (from-to)225-232
Number of pages8
JournalJournal of biochemistry
Volume128
Issue number2
DOIs
Publication statusPublished - Jan 1 2000

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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