Conformational Analysis of Two Cyclic Analogs of Angiotensin: Implications for the Biologically Active Conformation

Gregory V. Nikiforovich, Garland R. Marshall, Jeff L.F. Kao, Krystyna Plucinska, Wei Jun Zhang

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Conformations of two cyclic analogs of angiotensin (Asp1-Arg2-Val3-Tyr4-Val/Ile5-His6-Pro7- Phe8, AT), cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT, were studied, independently employing two complementary techniques, energy calculations and NMR measurements in DMSO solution. NMR data were indicative of well-defined solution conformations for the cyclic moieties of cyclo [Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT, including the ϕ values for the Cys3/HCys3 and Tyr4 residues, as well as the χ1 value for the Tyr4 residue. Solution conformations for the exocyclic linear parts of both molecules cannot be described by the NMR data with the same precision. At the same time, independent energy calculations revealed the same conformations of cyclic moieties of cyclo [Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT among low-energy conformers for both peptides. Moreover, the same conformations are compatible with the model of AT receptor-bound conformation (Nikiforovich & Marshall, 1993), which assumes the particular spatial arrangement of aromatic moieties of Tyr4, His6, and Phe8 residues and the C-terminal carboxyl. These conformers of cyclo [Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT contain “an open turn” in the backbone of the Tyr4-Val5 residues, instead of the earlier proposed β-like reversal, thus confirming the suggestion that the conformation(s) ensuring binding of AT analogs with specific receptors should not be described in terms of a unique backbone conformer.

Original languageEnglish
Pages (from-to)3591-3598
Number of pages8
JournalBiochemistry
Volume33
Issue number12
DOIs
StatePublished - Mar 1 1994

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