Multiple binding modes for the receptor-bound conformations of cyclic AII agonists

• Published in: Journal of medicinal chemistry Vol. 36; no. 13; pp. 1902 - 1913
• Main Authors: Plucinska, Krystina, Kataoka, Takahiro, Yodo, Mitsuaki, Cody, Wayne L, He, J. X, Humblet, Christine, Lu, G. H, Lunney, Elizabeth, Major, Terry C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.06.1993
• Subjects: Amino Acid Sequence; Angiotensin II - analogs & derivatives; Angiotensin II - chemical synthesis; Angiotensin II - chemistry; Angiotensin II - metabolism; Animals; Biological and medical sciences; Cyclization; Female; Hormones. Endocrine system; In Vitro Techniques; Liver - metabolism; Medical sciences; Molecular Sequence Data; Pharmacology. Drug treatments; Protein Conformation; Rabbits; Rats; Receptors, Angiotensin - metabolism; Uterus - metabolism; Vasoconstriction - drug effects; Agonist; Peptide bond; Cyclic peptides; Liver; Peptide hormone; In vitro; In vivo; Biological fixation; Vasomotricity; Uterus; Disulfide bond; Analog; Animal; Blood vessel; Angiotensin II; Chemical synthesis; Conformation; Hormonal receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00065a013

Angiotensin II, Asp-Arg-Val-Tyr-His-Pro-Phe, binds its receptor with a postulated turn centered at residue four. Analogs of angiotensin II which contain a disulfide bridge between the side chains of residues 3 and 5 retain significant activity consistent with this hypothesis. Incorporation of 4-mercaptoproline residues, a hybrid, or chimeric amino acid which combines the properties of proline and homocysteine, into either of these positions with analogous disulfide bridges allows retention of high affinity for the receptor. These more highly constrained bicyclic systems give new insight into the details of molecular recognition of residues 3-5 of angiotensin by the receptor. Retention of activity by the antiparallel dimer of [Sar1,Cys3,5]-AII in which the peptide backbone is held in an extended conformation was unexpected. Analysis of the conformational constraints imposed in these active analogs suggests that AII agonists bind to their receptor with different backbone conformations in the region of the central tyrosine residue.