Advances in the allostery of angiotensin II type 1 receptor

Abstract

Angiotensin II type 1 receptor (AT1R) is a promising therapeutic target for cardiovascular diseases. Compared with orthosteric ligands, allosteric modulators attract considerable attention for drug development due to their unique advantages of high selectivity and safety. However, no allosteric modulators of AT1R have been applied in clinical trials up to now. Except for the classical allosteric modulators of AT1R such as antibody, peptides and amino acids, cholesterol and biased allosteric modulators, there are non-classical allosteric modes including the ligand-independent allosteric mode, and allosteric mode of biased agonists and dimers. In addition, finding the allosteric pockets based on AT1R conformational change and interaction interface of dimers are the future of drug design. In this review, we summarize the different allosteric mode of AT1R, with a view to contribute to the development and utilization of drugs targeting AT1R allostery.

Keywords: Allosteric pocket; Allostery; Angiotensin II type 1 receptor; Biased ligands; Conformation; Dimers.

Fig. 1

The protein structure of human AT1R. Secondary structure of human AT1R with depiction of different motifs and important sites. Cys18–Cys274, the disulfide bond, stabilizes the N terminus and ECL3. And Cys101–Cys180 stabilizes TM3 and ECL2. The DRY motif and NPxxY motif, the microswitches of AT1R, are considered to participate in receptor activation. The interaction, N111^3.35 hydrogen bonds with N295^7.46, stabilizes the inactive state of AT1R.

Fig. 2

Allosteric modulators and pockets of AT1R. A AT110il and CLR are allosteric modulators of AT1R. B The active and inactive states of AT1R shows significant structural change in the binding site of AT1R-AAs. C A cryptic allosteric pocket is formed during MD simulation. D1) S1I8-bound AT1R with allosteric compound DCP1 and AT1R-AAs binding epitope are highlighted. D2) The cartoon picture of D1). E1) A potential cryptic allosteric pocket P6 is observed by using Fpocket. P6 is only identified during the movement of H8. E2) The cartoon picture of E1).

Fig. 3

Comparison of the allosteric structures of human AT1R bound to different ligands. A Overall conformational changes in human AT1R with blocker ZD7155 (PDB ID: 4YAY, green), β-arrestin biased ligand TRV026 (PDB ID: 60S2, yellow) and endogenous agonist AngII (PDB ID: 6OS0, pink). In the active state, TM5 and TM6 move out of AT1R whereas TM7 moves inward of the receptor. Helix 8 adopts a position parallel to the membrane compared to the inactive conformation bent away from the membrane. Viewing from the extracellular side, TM5 and TM7 move inward of inactive AT1R. B Superimposed structural details of AT1R induced by different ligands. The bulky phenylalanine of AngII at position 8 pushes L112^3.36 inward and Y292^7.43 in a relocation. A hydrogen bond between N295^7.46 and N111^3.35 breaks, and the two residuces move inward. However, due to TRV026 being less deeply into the binding pocket of AT1R, it has very little effect on movement of these residuces except for N295^7.46. C The alternative conformation is chosen when TM7 points toward TM3, and the canonical active conformation is chosen when TM7 points toward TM2.

Fig. 4

Allostery of AT1R dimers. A The heterodimers formed by AT1R with other 7TM receptors could enhance or B decrease signaling capabilities. C New signaling of AT1R/α_2CAR heterodimer. D Asymmetry of AT1R/FP heterodimer. E The interface between the homodimer of AT1R (PDB ID: 6do1) is constituted by ECL1, TM1, TM2, TM3, and Helix 8.