Role of the NH2-terminal domain of angiotensin II (ANG II) and [Sar1]angiotensin II on conformation and activity. NMR evidence for aromatic ring clustering and peptide backbone folding compared with [des-1,2,3]angiotensin II.

The role of the NH2 termini of angiotensin II (ANG II) and [Sar1]ANG II on conformation and activity were examined by proton NMR two-dimensional-J-correlated spectroscopy and one-dimensional nuclear Overhauser effect studies in the relatively nonpolar "receptor-simulating" environment provided by dimethyl sulfoxide-d6, using the biologically inactive COOH-terminal pentapeptide [des1,2,3]ANG II as control. Irradiation of C alpha H, C2H, and C4H proton resonances in ANG II and [Sar1]ANG II resulted in enhancements of Tyr and Phe ring proton resonances, indicating that the three aromatic rings cluster together. Very strong enhancements (17-22%) of the C alpha Y proton resonance in ANG II and [Sar1]ANG II upon irradiation of the C alpha H proton resonance, and vice versa, revealed that a Tyr-Ile-His bend is a predominant feature of the conformation of the two agonists. In contrast, saturation of the C alpha H and C alpha Y proton resonances in the control pentapeptide [des-1,2,3]ANG II did not produce, respectively, any C alpha Y or C alpha H proton nuclear Overhauser effect enhancement, illustrating the absence of a Tyr-Ile-His bend in the truncated ANG II peptide. The present findings indicate that the NH2-terminal domain of ANG II appears to have an essential role in generating the biologically active charge relay conformation of the hormone.