On the molecular basis of the recognition of angiotensin II (AII)

Abstract

The high-resolution 3D structure of the octapeptide hormone angiotensin II (AII) in aqueous solution has been obtained by simulated annealing calculations, using highresolution NMR-derived restraints. After final refinement in explicit water, a family of 13 structures was obtained with a backbone RMSD of 0.73 ± 0.23 Å . AII adopts a fairly compact folded structure, with its C-terminus and N-terminus approaching to within 7.2 Å of each other. The side chains of Arg2, Tyr4, Ile5 and His6 are oriented on one side of a plane defined by the peptide backbone, and the Val3 and Pro7 are pointing in opposite directions. The stabilization of the folded conformation can be explained by the stacking of the Val3 side chain with the Pro7 ring and by a hydrophobic cluster formed by the Tyr4, Ile5 and His6 side chains. Comparison between the NMR-derived structure of AII in aqueous solution and the refined crystal structure of the complex of AII with a high-affinity mAb (Fab131) [Garcia, K.C., Ronco, P.M., Verroust, P.J., Brunger, A.T., Amzel, L.M. (1992) Science 257, 502-507] provides important quantitative information on two common structural features: (a) a U-shaped structure of the Tyr4-Ile5-His6-Pro7 sequence, which is the most immunogenic epitope of the peptide, with the Asp1 side chain oriented towards the interior of the turn approaching the C-terminus; (b) an Asxturn-like motif with the side chain aspartate carboxyl group hydrogen-bonded to the main chain NH group of Arg2. It can be concluded that small rearrangements of the epitope 4-7 in the solution structure of AII are required by a mean value of 0.76 ± 0.03 Å for structure alignment and 1.27 ± 0.02 Å for sequence alignment with the X-ray structure of AII bound to the mAb Fab131. These data are interpreted in terms of a biological ÔnucleusÕ conformation of the hormone in solution, which requires a limited number of structural rearrangements for receptor-antigen recognition and binding.Keywords: angiotensin II; monoclonal antibody; NMR; peptide structure; VIb turn.Angiotensin II (AII), the main effector octapeptide hormone (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8) of the renin-angiotesin system [1], exerts a variety of actions on different target organs via specific receptors designated AT 1 and AT 2 [2,3]. Most of the known physiological effects of AII have been attributed to AT 1 , e.g. vasoconstriction, aldosterone release, renal sodium reabsorption, as well as central osmoregulatory actions, including the release of pituitary hormones into the circulation and growth stimulation in various cell types. These effects constitute the role of angiotensin peptides as neuromodulators/neurotransmitters in the brain. Because of the variety of biological and physiological actions of AII in various tissues, intensive research is required to determine the structural features of this phylogenetic hormone. This should provide the structural basis for the biological pathway of conformationinformation-transformation.For peptide ligand-receptor interactions, there are three genera...

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

“…1 Ang II is an octapeptide hormone (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8, DRVYIHPF) that has been studied for several decades in the structure-dependent activity of the biological pathway of the Ang II receptor. [2][3][4][5][6][7][8][9][10][11][12][13] Free Ang II molecular structures in solutions have been investigated with a variety of techniques. The results have been reported as β-turn, random coil, hair-pin and other structures.…”

“…The results have been reported as β-turn, random coil, hair-pin and other structures. [2][3][4][5][6][7][8] The structures of Ang II complexed with a receptor have been reported as a hair-pin or an extended structure in NMR and crystallography studies. [9][10][11][12][13] It is evident that several reports are not consistent with each other and that no clear agreement exists regarding the biologically active structure of Ang II during the biological process.…”

Antiplasmodial Activity of Angiotensin II Analogs

“…The deletion of valine decreased the antiplasmodial activity by 23% [4]. The decrease in antiplasmodial activity may impede the interaction between the proline and valine in the chain [7]. This promotes the stabilization of the folded conformation of AII as evidenced by the conformational change in the circular dichroism.…”

“…Analogs 1 -[His 1 ]-AII and 8 -[Asn 1 ]-AII activities were 35% and 71% of baseline, respectively. This relative decrease may be because AII has a compact folded structure due to the proximity of their amino terminus and carboxy-terminus [7].…”

Conformational properties of angiotensin II and its active and inactive TOAC‐labeled analogs in the presence of micelles. Electron paramagnetic resonance, fluorescence, and circular dichroism studies

“…3,[8][9][10][11][12][13][14][15][16][17][19][20][21][22][23][24][25] At present, it is widely accepted that AII has a flexible structure resulting from the equilibrium between several interconverting conformations. At low temperature, in aqueous solution, AII adopts a hairpin conformation where the N-and C-termini are at a distance of 7.2 Å .…”