The angiotensin II receptor of the AT1-type has been modeled starting from the experimentally determined three-dimensional structure of bacteriorhodopsin as the template. Intermediate 3D structures of rhodopsin and beta 2-adrenergic receptors were built because no direct sequence alignment is possible between the AT1 receptor and bacteriorhodopsin. Docking calculations were carried out on the complex of the modeled receptor with AII, and the results were used to analyze the binding possibilities of DuP753-type antagonistic non-peptide ligands. We confirm that the positively charged Lys199 on helix 5 is crucial for ligand binding, as in our model; the charged side chain of this amino acid interacts strongly with the C-terminal carboxyl group of peptide agonists or with the acidic group at the 2'-position of the biphenyl moiety of DuP753-type antagonists. Several other receptor residues which are implicated in the binding of ligands and the activation of receptor by agonists are identified, and their functional role is discussed. Therefore, a plausible mechanism of receptor activation is proposed. The three-dimensional docking model integrates most of the available experimental observations and helps to plan pertinent site-directed mutagenesis experiments which in turn may validate or modify the present model and the proposed mechanism of receptor activation.

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4 conformational search using high-temperature molecular dynamics on angiotensin I1 (AII) and on two cyclic S-S bridged analogs. namely [ H c~~.~] A I I and [Cys3.']AII, In conjunction with a cluster analysis based on the similarities of the three-dimensional patterns of the binding and activation elements. has led to putative A11 receptor-bound conformations. These conformations are characterized by a compact folded shape of the peptide backbone, and by particular relative positions of the four pharmacophore groups, namely the aromatic moieties of the Tyr4, His6 and Phe* residues, and the C-terminal carboxyl group. This compact folded shape, arising from attractive electrostatic interactions between the desolvated N-and C-terminal groups. is similar to the crystallographically determined conformation of ,411 bound to the antibody Fab receptor. 0 Munksgaard 1995. KCJ. it.ortls; angiotensin 11 (AII): biologicall! actn e conformation; clusrcr anal! sis; conformatIona1 search; molecular dynamics Srritcr. THEOCHEM. To be submitted 32. 898-903 aga. H.

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