Gating Mechanism for Biased Agonism at Angiotensin II Type 1 Receptors

<p dir="ltr">For the interaction of angiotensin II (AngII) with AngII type 1 receptors (AT₁R), two potential proton hopping pathways have been identified, each associated with distinct physiological outcomes. The octapeptide AngII (Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-Pro⁷-Phe⁸) appears to form a charge relay system (CRS) in solution in which the C-terminal carboxylate abstracts a proton from the His⁶ imidazole group, which, in turn, abstracts a proton from the Tyr⁴ hydroxyl (OH) group, creating a tyrosinate anion. When AngII binds to the AT₁R, the CRS can be reconstituted with D281 of the receptor taking up the role of the Phe⁸ carboxylate in the tripartite interaction, whilst the Phe⁸ carboxylate forms a salt bridge with K199 of the receptor. As a consequence, the Tyr⁴ OH of AngII is positioned with accessibility to either the Phe⁸ carboxylate (bound to K199) or the His⁶ imidazole (activated by D281), thereby creating a potential gating mechanism for AT₁R receptor signaling. This study summarizes evidence based on structure activity data for various analogs wherein Tyr⁴ OH interaction with His⁶ imidazole (CRS formation) leads to G protein sequestration and vasoconstriction, whereas Tyr⁴ OH interaction with Phe⁸ carboxylate (bound to K199) engenders arrestin-mediated vasodilation and receptor desensitization. These findings, combined with quantum mechanical (semiempirical) calculations of CRS proton transfer presented herein, provide insights for the therapeutic targeting of angiotensin receptor blockers (sartans) and the development of second-generation drugs (bisartans).</p>