A COMPUTER MODELING POSTULATED MECHANISM FOR ANGIOTENSIN-II RECEPTOR ACTIVATION

The angiotensin II receptor of the AT(1)-type has been modeled startin g from the experimentally determined three-dimensional structure of ba cteriorhodopsin as the template. Intermediate 3D structures of rhodops in and beta(2)-adrenergic receptors were built because no direct seque nce alignment is possible between the AT(1) receptor and bacteriorhodo psin. Docking calculations were carried out on the complex of the mode led receptor with AII, and the results were used to analyze the bindin g possibilities of DuP753-type antagonistic non-peptide ligands. We co nfirm that the positively charged Lys(199) on helix 5 is crucial for l igand binding, as in our model; the charged side chain of this amino a cid interacts strongly with the C-terminal carboxyl group of peptide a gonists or with the acidic group at the 2'-position of the biphenyl mo iety of DuP753-type antagonists. Several other receptor residues which are implicated in the binding of ligands and the activation of recept or 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 e xperimental observations and helps to plan pertinent site-directed mut agenesis experiments which in turn may validate or modify the present model and the proposed mechanism of receptor activation.