ROLE OF THE NH2-TERMINAL DOMAIN OF ANGIOTENSIN-II (ANG-II) AND [SAR(1)]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 [Sar(1)]ANG II on conformation and activity were examined by proton NMR two-dimen sional-J-correlated spectroscopy and one-dimensional nuclear Overhause r effect studies in the relatively nonpolar ''receptor-simulating'' en vironment provided by dimethyl sulfoxide-d(6), using the biologically inactive COOH-terminal pentapeptide [des1,2,3]ANG II as control. Irrad iation of C alpha H, C2H, and C4H proton resonances in ANG II and [Sar (1)]ANG II resulted in enhancements of Tyr and Phe ring proton resonan ces, indicating that the three aromatic rings cluster together. Very s trong enhancements (17-22%) of the C alpha Y proton resonance in ANG I I slid [Sar(1)]ANG II upon irradiation of the C alpha H proton resonan ce, and vice versa, revealed that a Tyr-Ile-His bend is a predominant feature of the conformation of the two agonists. In contrast, saturati on of the C alpha H and C alpha Y proton resonances in the control pen tapeptide [des1,2,3]ANG II did not produce, respectively, any C alpha Y or C alpha H proton nuclear Overhauser effect enhancement, illustrat ing 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 activ e charge relay conformation of the hormone.