Structural basis for selectivity and diversity in angiotensin II receptors

Abstract

Angiotensin II receptors, AT1R and AT2R, serve as key components of the renin-angiotensin-aldosterone system. While AT1R plays a central role in the regulation of blood pressure, the function of AT2R is enigmatic with a variety of reported effects. To elucidate the mechanisms for the functional diversity and ligand selectivity between these receptors, we report crystal structures of the human AT2R bound to an AT2R-selective and an AT1R/AT2R-dual ligand, respectively, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins/β-arrestins, in agreement with the lack of signaling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the interactions critical for ligand binding and selectivity. Our results thus provide insights into the structural basis for distinct functions of the angiotensin receptors, and may guide the design of novel selective ligands.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…The crystal structure of human AT 2 R with ligands has recently been reported. The data suggest an active-like conformation, but with the helix VIII preventing recruitment of G proteins or ␤-arrestins, which is in agreement with lack of signaling responses in standard assays (1244). While decades of research have established the distinct signaling mechanisms of AT 1 R and AT 2 R, future experiments should establish precise signaling mechanisms by which ANG II modulates physiological and pathophysiological functions. Please also refer to recent review articles for accumulating literature regarding the protections and potential mechanisms utilized by AT 2 R against hypertension, vascular remodeling, and end organ damage in heart, kidney, and brain (168, 660, 1011).…”

Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

“…G-protein-coupled receptors (GPCRs) have proven to be a successful therapeutic target accounting for ~30–50% marketed drugs. Angiotensin-II (ang-II) type 2 receptor (AT 2 R) 1–4 and receptor Mas (MasR) 5–9 belong to non-classical GPCR family 10 and mediate functions such as diuresis, natriuresis, vasorelaxation and blood pressure reduction in various animal models. The AT 2 R 3 and MasR 5,7,11,12 also show overlapping signaling in terms of nitric oxide (NO) formation and inhibiting Na + ,K + -ATPase activity in renal proximal tubules.…”

Small‐molecule AT2 receptor agonists

“…Furthermore, heteroarylacyl groups are suitable as para substituents and benzylamide, acetic acid amide, and benzoic acid amide functions in the para position can frequently furnish high affinity selective ligands. The recently reported crystal structures of human AT2R bound to an AT2R‐selective ligand and to an AT1R/AT2R dual ligand provide important structural information that will be very useful in the design of new selective high‐affinity ligands to AT2R …”