Angiotensin II vs Its Type I Antagonists:  Conformational Requirements for Receptor Binding Assessed from NMR Spectroscopic and Receptor Docking Experiments

The conformations of three angiotensin II (AII) peptide antagonists ([Sar1]-AII(1−7)-NH2, [Sar1,Val5,Ala8]-AII and the AII antipeptide, [Glu1,Gly2,Val5,Val8]-AII) were assessed in a lipid medium. A common backbone turn was identified through modeling and spectroscopic studies. The His6 residue acted as a pivoting point beyond which each peptide adopted two distinct conformations. One principle conformer resembled that previously determined for AII while the other was designated as an AII antagonist like conformer. A computational overlay between the nonpeptide antagonist, Losartan, and both the AII and the AII like conformation of [Sar1,Val5,Ala8]-AII revealed common pharmacophoric points with RMS deviations between 1 and 1.5 Å. Both the AII conformer and the AII antagonist like conformer of [Sar1,Val5,Ala8]-AII were docked into a model of the AT1 receptor. Receptor residue Phe289 and Asp281 provided good contact points for both peptides. Some differences were also noted. The terminal carboxyl of AII contacted Lys199 of the receptor while that of [Sar1,Val5,Ala8]-AII bridged Arg23 at the top of helix 1. The Asp1 side chain of AII interacted with His183 of the receptor.