Multiple Binding Modes for the Receptor-Bound Conformations of Cyclic AII Agonists

Krystina Plucinska, Takahiro Kataoka, Mitsuaki Yodo, Wayne L. Cody, J. X. He, Christine Humblet, G. H. Lu, Elizabeth Lunney, Terry C. Major, Robert L. Panek, Pamela Schelkun, Richard Skeean, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish
Pages (from-to)1902-1913
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number13
StatePublished - 1993


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