# Gating Mechanism for Biased Agonism at Angiotensin II Type 1 Receptors

## TL;DR

This paper explains how angiotensin II interacts with its receptor to produce different physiological effects through a proton transfer mechanism.

## Contribution

The study identifies a gating mechanism in angiotensin II type 1 receptors based on proton transfer pathways and their physiological outcomes.

## Key findings

- Tyr4 OH interaction with His6 imidazole leads to G protein sequestration and vasoconstriction.
- Tyr4 OH interaction with Phe8 carboxylate leads to arrestin-mediated vasodilation and receptor desensitization.
- Quantum mechanical calculations support the proton transfer mechanism in angiotensin receptor signaling.

## Abstract

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).