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The Angiotensin II AT₁ Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure

Department of Biophysics, Escola Paulista de Medicina, Federal University of São Paulo; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto; and Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil

The most prevalent physiological effects of ANG II, the main product of the renin-angiotensin system, are mediated by the AT₁ receptor, a rhodopsin-like AGPCR. Numerous studies of the cardiovascular effects of synthetic peptide analogs allowed a detailed mapping of ANG II's structural requirements for receptor binding and activation, which were complemented by site-directed mutagenesis studies on the AT₁ receptor to investigate the role of its structure in ligand binding, signal transduction, phosphorylation, binding to arrestins, internalization, desensitization, tachyphylaxis, and other properties. The knowledge of the high-resolution structure of rhodopsin allowed homology modeling of the AT₁ receptor. The models thus built and mutagenesis data indicate that physiological (agonist binding) or constitutive (mutated receptor) activation may involve different degrees of expansion of the receptor's central cavity. Residues in ANG II structure seem to control these conformational changes and to dictate the type of cytosolic event elicited during the activation. 1) Agonist aromatic residues (Phe⁸ and Tyr⁴) favor the coupling to G protein, and 2) absence of these residues can favor a mechanism leading directly to receptor internalization via phosphorylation by specific kinases of the receptor's COOH-terminal Ser and Thr residues, arrestin binding, and clathrin-dependent coated-pit vesicles. On the other hand, the NH₂-terminal residues of the agonists ANG II and [Sar¹]-ANG II were found to bind by two distinct modes to the AT₁ receptor extracellular site flanked by the COOH-terminal segments of the EC-3 loop and the NH₂-terminal domain. Since the [Sar¹]-ligand is the most potent molecule to trigger tachyphylaxis in AT₁ receptors, it was suggested that its corresponding binding mode might be associated with this special condition of receptors.

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