Interaction mode of the phe-phenyl group of thrombin receptor-tethered ligand SFLLRNP in receptor activation

Takeru Nose, Tsugumi Fujita, Masahide Nakajima, Yoshihisa Inoue, Tommaso Costa, Yasuyuki Shimohigashi

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Phenylalanine at position 2 of thrombin receptor-tethered ligand peptide (SFLLRNP) is crucially important for the activation of thrombin receptor. Its substitution by para-fluorophenylalanine [(p-F)Phe] enhanced several times the activity in human epithelial-like SH-EP cells. To clarify the interaction mode of Phe-2-phenyl in receptor activation, a series of analogs having chemical modifications on the benzene ring of Phe-2 were synthesized and examined for their ability to induce the aggregation of human platelets. When the fluorine atom was placed at the meta or ortho position, the resulting analogs exhibited considerably diminished activity (about 10-20% of para-derivative), indicating that the substitution is allowed only at the para position. The derivative with pentafluorophenylalanine was totally devoid of activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement was observed for analogs with para-chloro-, bromo-, or iodophenylalanine, indicating the importance of the high electronegativity of fluorine to intensify the dipole of CH(s) remaining in the Phe-2-benzene ring. Inactivity of analogs having para-iodophenylalanine and homophenylalanine indicated the importance of the size of para substituents, and the placement of hydroxyl, nitro, and trifluoromethyl groups at the para position led to no activity. The interaction of Phe-2 of SFLLRNP appeared to be structurally restricted to a limited space in the receptor. The results suggested the presence of face-to-edge π-π interaction based upon the CH/π interaction between the ligand Phe-2-phenyl group and the receptor aromatic group.

Original languageEnglish
Pages (from-to)354-358
Number of pages5
JournalJournal of Biochemistry
Volume124
Issue number2
DOIs
Publication statusPublished - Jan 1 1998

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thrombin receptor peptide SFLLRNP
Thrombin Receptors
Benzene
Fluorine
Chemical activation
Ligands
p-Fluorophenylalanine
Substitution reactions
Derivatives
Atoms
Electronegativity
Chemical modification
Platelets
Phenylalanine
Platelet Aggregation
Human Activities
Hydroxyl Radical
Hydrogen
Agglomeration
Peptides

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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Interaction mode of the phe-phenyl group of thrombin receptor-tethered ligand SFLLRNP in receptor activation. / Nose, Takeru; Fujita, Tsugumi; Nakajima, Masahide; Inoue, Yoshihisa; Costa, Tommaso; Shimohigashi, Yasuyuki.

In: Journal of Biochemistry, Vol. 124, No. 2, 01.01.1998, p. 354-358.

Research output: Contribution to journalArticle

Nose, Takeru ; Fujita, Tsugumi ; Nakajima, Masahide ; Inoue, Yoshihisa ; Costa, Tommaso ; Shimohigashi, Yasuyuki. / Interaction mode of the phe-phenyl group of thrombin receptor-tethered ligand SFLLRNP in receptor activation. In: Journal of Biochemistry. 1998 ; Vol. 124, No. 2. pp. 354-358.
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N2 - Phenylalanine at position 2 of thrombin receptor-tethered ligand peptide (SFLLRNP) is crucially important for the activation of thrombin receptor. Its substitution by para-fluorophenylalanine [(p-F)Phe] enhanced several times the activity in human epithelial-like SH-EP cells. To clarify the interaction mode of Phe-2-phenyl in receptor activation, a series of analogs having chemical modifications on the benzene ring of Phe-2 were synthesized and examined for their ability to induce the aggregation of human platelets. When the fluorine atom was placed at the meta or ortho position, the resulting analogs exhibited considerably diminished activity (about 10-20% of para-derivative), indicating that the substitution is allowed only at the para position. The derivative with pentafluorophenylalanine was totally devoid of activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement was observed for analogs with para-chloro-, bromo-, or iodophenylalanine, indicating the importance of the high electronegativity of fluorine to intensify the dipole of CH(s) remaining in the Phe-2-benzene ring. Inactivity of analogs having para-iodophenylalanine and homophenylalanine indicated the importance of the size of para substituents, and the placement of hydroxyl, nitro, and trifluoromethyl groups at the para position led to no activity. The interaction of Phe-2 of SFLLRNP appeared to be structurally restricted to a limited space in the receptor. The results suggested the presence of face-to-edge π-π interaction based upon the CH/π interaction between the ligand Phe-2-phenyl group and the receptor aromatic group.

AB - Phenylalanine at position 2 of thrombin receptor-tethered ligand peptide (SFLLRNP) is crucially important for the activation of thrombin receptor. Its substitution by para-fluorophenylalanine [(p-F)Phe] enhanced several times the activity in human epithelial-like SH-EP cells. To clarify the interaction mode of Phe-2-phenyl in receptor activation, a series of analogs having chemical modifications on the benzene ring of Phe-2 were synthesized and examined for their ability to induce the aggregation of human platelets. When the fluorine atom was placed at the meta or ortho position, the resulting analogs exhibited considerably diminished activity (about 10-20% of para-derivative), indicating that the substitution is allowed only at the para position. The derivative with pentafluorophenylalanine was totally devoid of activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement was observed for analogs with para-chloro-, bromo-, or iodophenylalanine, indicating the importance of the high electronegativity of fluorine to intensify the dipole of CH(s) remaining in the Phe-2-benzene ring. Inactivity of analogs having para-iodophenylalanine and homophenylalanine indicated the importance of the size of para substituents, and the placement of hydroxyl, nitro, and trifluoromethyl groups at the para position led to no activity. The interaction of Phe-2 of SFLLRNP appeared to be structurally restricted to a limited space in the receptor. The results suggested the presence of face-to-edge π-π interaction based upon the CH/π interaction between the ligand Phe-2-phenyl group and the receptor aromatic group.

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