The acidic pharmacophores of selective ligands bind to Lys and His of the AT receptor (Noda, K., Saad, Y., Kinoshita, A., Boyle, T. P., Graham, R. M., Husain, A., and Karnik, S.(1995) J. Biol. Chem. 270, 2284-2289). In this report we examine how interactions between these residues and agonists activate inositol phosphate production in transiently transfected COS-1 cells. [Sar] angiotensin (Ang II) II and [Sar]Ang II-amide stimulated a 5-fold inositol phosphate response from wild-type AT receptor. The peptide antagonist [Sar,Ile]Ang II and the non-peptide agonist L-162,313 produced a partial but saturating response. Stimulation of wild-type receptor by [Sar]Ang II-amide and the mutant K199Q and K199A receptors by [Sar]Ang II demonstrates that AT receptor activation is not critically dependent on the ion-pairing of the -COOH group of Ang II with Lys. The mutation of His produced diminished inositol phosphate response without commensurate change in binding affinity of ligands. The His side chain is critical for maximal activation of the AT receptor, although isosteric Gln substitution is sufficient for preserving the affinity for Phe-substituted analogues of [Sar]Ang II. Therefore, AT receptor activation requires interaction of Phe side chain of Ang II with His, which is achieved by docking the -COOH group of Phe to Lys. Furthermore, non-peptide agonists interact with Lys and His in a similar fashion.

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