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)-NH(2), [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 A. Both the AII conformer and the AII antagonist like conformer of [Sar1,Val5,Ala8]-AII were docked into a model of the AT(1) 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.
Wilkes
Brian C
BC
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, H2W 1R7 Canada.
Masaro
Laurent
L
Schiller
Peter W
PW
Carpenter
Katharine A
KA
D000803:Angiotensin I / Q000737:chemistry*; D000804:Angiotensin II / Q000737:chemistry*; D057911:Angiotensin Receptor Antagonists; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011945:Receptors, Angiotensin / Q000737:chemistry*; D012504:Saralasin / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C058708:angiotensin II amide (1-7), Sar(1)-; C073965:glutamyl-glycyl-valyl-tyrosyl-valyl-histidyl-prolyl-valine; D000803:Angiotensin I; D012504:Saralasin