Edge-to-face CH/pi interaction between ligand Phe-phenyl and receptor aromatic group in the thrombin receptor activation.
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 p 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 [(F(2))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/pi 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/pi 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/pi interaction, and to strengthen the CH/pi interaction.
Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
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A
Matsushima
T
T
Fujita
T
T
Nose
Y
Y
Shimohigashi
D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D018179:Receptors, Thrombin / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D008024:Ligands; D018179:Receptors, Thrombin; D010649:Phenylalanine