title: 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 protein-independently through β-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.
authors.affiliation: Pharmacology UnitFaculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, MalaysiaDivision of Cardiovascular and Renal ProductsCenter for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA pbala2006@gmail.com.
authors.forename: Pitchai
authors.initials: P
authors.lastname: Balakumar
authors.affiliation: Pharmacology UnitFaculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, MalaysiaDivision of Cardiovascular and Renal ProductsCenter for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA.
authors.forename: Gowraganahalli
authors.initials: G
authors.lastname: Jagadeesh
mesh_terms: D000596:Amino Acids; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000596:Amino Acids; D047228:Angiotensin II Type 1 Receptor Blockers; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II
keywords: AT1 receptor; angiotensin II; renin–angiotensin system; β-arrestin