Structural studies on endothelin receptor subtype B specific agonist IRL 1620 [suc-[Glu9, Ala11,15]ET-1(8-21)] and its analogs with dipalmitoyl phosphatidylcholine vesicles by NMR spectroscopy.
IRL 1620 ¿suc-[Glu9,Ala11,15]ET-1(8-21)¿ is a potent and specific agonist for the ET(B) receptor. Five analogs of IRL 1620 were synthesized in this study. These were all C-terminal linear peptides of endothelin 1 (ET-1) comprising 14 amino acid residues and exhibiting highly potent ET(B) receptor binding affinities. The peptides consisted of three pairs and each component of the pairs differed from its partner in only the 18th residue, i.e. Asp was replaced by Gly. The replacements resulted in more than a 10-fold increase in affinity to the ET(A) receptor. The structures of these peptides were investigated in the presence of phospholipid vesicles (dipalmitoyl phosphatidylcholine) by NMR spectroscopy. By the replacement of Asp by a less bulky Gly, the C-terminal tripeptide region folded back toward the helical region, making it shorter than the Asp-substituted peptide helical region. Such a folded conformational feature may explain the increased binding affinity to ET(A) receptor.
Katahira
R
R
International Research Laboratories, Ciba-Geigy Japan Ltd., Takarazuka.
Umemura
I
I
Takai
M
M
Oda
K
K
Okada
T
T
Nosaka
A Y
AY
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism*; D000595:Amino Acid Sequence; D019332:Endothelin-1 / Q000031:analogs & derivatives* / Q000737:chemistry; D016232:Endothelins / Q000737:chemistry*; D008081:Liposomes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D019332:Endothelin-1; D016232:Endothelins; D008081:Liposomes; D010446:Peptide Fragments; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C074308:sovateltide; D015060:1,2-Dipalmitoylphosphatidylcholine