Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34

Abstract

Functional advances have guided our knowledge of physiological and fatal pathological mechanisms of the hormone angiotensin II (AngII) and its antagonists. Such studies revealed that tissue response to a given dose of the hormone or its antagonist depends on receptors that engage the ligand. Thus, we need to know much more about the structures of receptor-ligand complexes at high resolution. Recently, X-ray structures of both AngII receptors (AT₁ and AT₂ receptors) bound to peptide and non-peptide ligands have been elucidated, providing new opportunities to examine the dynamic fluxes in the 3D architecture of the receptors, as the basis of ligand selectivity, efficacy, and regulation of the molecular functions of the receptors. Constituent structural motifs cooperatively transform ligand selectivity into specific functions, thus conceptualizing the primacy of the 3D structure over individual motifs of receptors. This review covers the new data elucidating the structural dynamics of AngII receptors and how structural knowledge can be transformative in understanding the mechanisms underlying the physiology of AngII.

Keywords: AT1 receptor; AT2 receptor; AngII; G protein; GPCR; allosteric modulation; autoantibody; ligand selectivity; β-arrestin.

Fig. 1.

(A) 2D cartoon depiction of AngII binding to AT1R leading to recruitment of G protein and/or β-arrestin. ARBs can block AngII binding to AT1 receptor and consequently the signaling. (B) Superimposition of AT1 and AT2 receptor structures showing the location of bound AngII in both receptors. (C) Superimposed structure of BRIL-AT1 receptor (PDB id: 4yay) and alpha-fold modeled full length AT1 receptor structure. (D) Smaller access to othosteric site in BRIL-AT1 receptor structure and (E) Substantially larger access to orthosteric site seen in alpha-fold modeled full length AT1 receptor structure. (F) Superimposed structures of BRIL-AT2 receptor from crystallography (orange for AT2 receptor and magenta for BRIL) and AT2 receptor from model prediction by alpha-fold (blue). (G) Extracellular surface view of BRIL-AT2 receptor structure showing the open orthosteric pocket. (H) Extracellular surface view of the alpha-fold model AT2 receptor structure showing N-terminus covering the orthsteric pocket.

Fig. 2.

(A) Schema of intra-molecular events triggered by Phe8^AngII interaction with AT1 receptor which lead to receptor activation. (B) Superimposed structures of AT1 receptor’s inactive (cyan) and active (magenta) states with AngII shown in green. Select residues depicted to show change in their position in active state AT1 receptor. (C) Phe8^AngII pushes the side chain of L112^3.36 resulting in relocation of Y292^7.43 side chain. (D) Breakage of the ionic lock between N111^3.35 and N295^7.43. (E) Relocation of aromatic residues. (F) Arrows indicate outward movement of TM6, inward movement of TM7 and movement of helix-8 towards membrane surface.

Fig. 3.

(A) Schema showing that TRV026 lacking the bulky aromatic residue at position 8 does not perturb L112^3.36 and Y292^7.43 position and does not break N111^3.35 ionic bond with N295^7.43. However, it forms new H-bond with D74^2.50 as in active state structure. (B) Superimposed structures of AT1 receptor bound with AngII (PDB id: 6os0), and TRV026 (PDB id: 6os2) showing significant difference in movement of TM6. (C) Ile8^TRV026 exerts no effect on L112^3.36 and Y292^7.43. Position of N111^3.35 remain same as inactive state structure, however, it forms new H-bond with D74^2.50 like an active state structure. Position of residues in TRV026-bound structure (cyan) and inactive state (brown) indicates no change compared to AngII-bound state (magenta). (D) Strong interaction of K199^5.42 with Ile8^TRV026 carboxyl and Tyr4^TRV026 hydroxyl groups leads to pushing of H256^6.51 downward; and (E) relocation of aromatic residues as in AngII bound structure. (F) Conformation of Y226^ICL3 F301^7.52 were different from active structure.

Fig. 4.

(A) Superimposed structure of Olmesartan (cyan) bound AT1 receptor and compound 1 (yellow) and 2 (pink) bound AT2 receptor structure. Y^7.43 of AT1 receptor would cause steric hindrance to bind compound 1 and 2. F^7.43 of AT2 receptor would cause steric hindrance to bind olmesartan. AT1 receptor ligands i.e. ZD7511 (B) and Olmesartan (C) inserted in the binding pocket of AT2 receptor. Increase in distance between R^4.64 and Y^1.39 from the AT1 receptor ligands may also decrease the binding affinity towards AT2 receptor. AT2 receptor ligands compound 1 (D) and compound 2 (E) inserted in the binding pocket of AT1 receptor. T^4.60 to A^4.60 replacement may significantly decrease binding towards AT1 receptor.

Fig. 5.

(A) Superimposed structure of AT1 receptor in inactive (cyan) and active (magenta) conformation showing significant change in conformation in the AT1 receptor-AA binding site. Cryptic allosteric pocket was formed during the course of MD simulation. Allosteric pocket in inactive conformation (B) active conformation (C) and during MD simulation (D) are shown in red. (E) Cartoon structure of AT1 receptor bound with AngII and allosteric compound highlighting the AT1 receptor autoantibody binding epitope.