Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Abstract

The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT 1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT 1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT 1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT 1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G proteinindependently through b-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT 1 receptor.

Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

“…Although not directly tested in this study, one possible mechanism where by the AT1-AA can increase ANGII sensitivity is by binding to the 2 nd extracellular loop of the AT1 G-coupled receptor, creating bonds between transmembrane receptor domains 2 and 7, triggering a conformational change that will increase the binding affinity for ANG II 36, 46 . Another mechanism is by dimerization of the AT1R with the vasodepressor bradykinin receptor (B 2 ) 47 .…”

“…After this discovery numerous research has been performed, examining the role of AT1-AAs in the pathophysiology of preeclampsia 36–38 . This AT1-AA binds to and activates the AT1R, thereby increasing chronotropic events in cultured cardiomyocytes, very similarly to ANGII.…”

Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor

“…Angiotensin II (AngII) 5 type 1 receptor (AT 1 R) is a G protein-coupled receptor (GPCR), mainly found in heart, brain, liver, and kidneys, regulating normal blood pressure, as well as fluid and electrolyte homeostasis (1,2). Overstimulation of AT 1 R leads to diseases such as hypertension, cardiovascular hypertrophy, and fibrosis, whereas blocking the activity of AT 1 R lowers blood pressure (3,4).…”

“…Multiple studies suggest that such additional tissue-protective benefits from treatment with ARBs may be mediated by AT 1 R ␤-arrestin signaling, although the structural basis for differential activation of this mechanism by ARBs is unknown (8,10). AngII analogs, such as TRV120027, lacking G protein agonism but activating ␤-arrestin signaling, protect the heart and vasculature in a pathological setting better than common ARBs (2,8,9), suggesting the need for a better understanding of the mechanisms for functional selectivity of different AT 1 R ligands.…”

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

“…The first glimpse into the human AT 1 R crystal structure was recently provided and it was the first step towards that goal[50]. Unfortunately however, that crystal structure lacked the intracellular C-terminal tail of the receptor, which is exactly the AT 1 R region that interacts with βarrs [51]. …”