A review of mutagenesis studies of angiotensin II type 1 receptor, the three-dimensional receptor model in search of the agonist and antagonist binding site and the hypothesis of a receptor activation mechanism

OBJECTIVE: To seek the mechanism whereby agonists, competitive antagonists and insurmountable antagonists affect the receptor function differently, by reviewing recent mutagenesis studies of angiotensin II type 1 receptor (AT1) in which the binding of the agonist and antagonists and receptor signaling were affected. AT1 RECEPTOR STRUCTURE AND LIGAND BINDING SITES: We built a model of seven transmembrane spanning domains of the AT1 receptors using bacteriorhodopsin as a template. The carboxy terminal of angiotensin II binds to Lys199 in transmembrane domain 5, whereas the guanidinium group of Arg2 binds to Asp281 in transmembrane domain 7. Results of studies using mutagenesis supporting proposed ligand-docking models are discussed. HYPOTHESIS FOR THE LIGAND-INDUCED RECEPTOR SIGNALING MECHANISM: We submit a set of hypotheses for a mechanism whereby the ligand binding induces changes in the receptor conformation by the rotation of transmembrane helices as the initial event for the subsequent activation of a G protein. In this mechanism antagonists are not capable of rotating the helices but agonists are able to do so, which results in the formation of a hydrogen bond between Asp74 in transmembrane domain 2 and Tyr292 in transmembrane domain 7. This mechanism also provides plausible explanation for the activation of monoamine receptors. COMPETITIVE AND INSURMOUNTABLE ANTAGONISTS: Competitive antagonists share the same binding sites with agonists, but insurmountable antagonists do not, and binding of the latter does not preclude agonist binding, for example, to Asp281. CONCLUSION: This hypothesis of the intrareceptor signaling mechanism and the receptor model indicate that some amino acid residues essential for the signaling play their roles in the intrareceptor activation mechanism, whereas others participate directly in ligand binding.