Differential receptor binding characteristics of consecutive phenylalanines in micro-opioid specific peptide ligand endomorphin-2.
Endogenous opioid peptides consist of a conserved amino acid residue of Phe(3) and Phe(4), although their binding modes for opioid receptors have not been elucidated in detail. Endomorphin-2, which is highly selective and specific for the mu opioid receptor, possesses two Phe residues at the consecutive positions 3 and 4. In order to clarify the role of Phe(3) and Phe(4) in binding to the mu receptor, we synthesized a series of analogs in which Phe(3) and Phe(4) were replaced by various amino acids. It was found that the aromaticity of the Phe-beta-phenyl groups of Phe(3) and Phe(4) is a principal determinant of how strongly it binds to the receptor, although better molecular hydrophobicity reinforces the activity. The receptor binding subsites of Phe(3) and Phe(4) of endomorphin-2 were found to exhibit different structural requirements. The results suggest that [Trp(3)]endomorphin-2 (native endomorphin-1) and endomorphin-2 bind to different receptor subclasses.
Honda
Takeshi
T
Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
Shirasu
Naoto
N
Isozaki
Kaname
K
Kawano
Michiaki
M
Shigehiro
Daiki
D
Chuman
Yoshiro
Y
Fujita
Tsugumi
T
Nose
Takeru
T
Shimohigashi
Yasuyuki
Y
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D008024:Ligands; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000737:chemistry*; D013912:Threonine / Q000737:chemistry
D008024:Ligands; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D013912:Threonine; C105294:endomorphin 2; D010649:Phenylalanine