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Function

History

Searchers suspected since 70s the existence of different angiotensin receptors. But it was only at the end of 80s that searchers had tools to identify these two distinct trans-membrane receptors (AT1R and AT2R) ^[1]. Three labs discovered in the same time these two receptors so they were some confusion about the nomenclature. So in 1991 a group of searchers met in Baltimore under the presidency of Merlin Bumpus to define a coherent nomenclature. Finally, around 2015, researchers found the crystal structure of the receptor in complex with its antagonist ZD7155 and with an inverse agonist olmesartan^[2]. They used x-ray cryogenic-crystallography. They found similar conformation of the receptor when it is linked to the antagonist or to the inverse agonist. They also found conserved molecular recognition modes. So to complete the discovery, they realized some experiments with mutants to identify the different residues which interact with the ligand.

Structure (function relationship)

Primary and secondary structure

Human angiotensin receptor consists in a 376 amino acid string ^[3]. The protein is composed of 18 and 3 . Moreover, 7 alpha helix are made of a majority of hydrophobic amino acids and these helix are long enought to cross the membrane. These helix creat an which is situated into the membrane. So the human angiotensin receptor is an alpha helical transmembrane protein.

Ligand binding pocket

In the extracellular environement, there is a beta-hairpin in conjugaison with two extracellular disulfure bridges. This structure is responsible for the oppening and the locking of the ligand binding pocket ^[4]. The ligand go into an created into the membrane thanks to the 7 alpha helix which creat gate between the membrane and the extracellular environnement.

G protein-binding site

When Angiotensine II bind to the angiotensine receptor in the ligand binding pocket, the conformation of the transmembrane domain change which creat a cytosolic cleft for binding and activating of G proteins. In this cleft we can find several conserved residues which form functional motifs present in all GPCRs ^[5].

Interaction with drugs

Olmesartan, candesartan, telmisartan, and valsartan

Olmesartan anchored to ATR1 by the residues , and . Those amino acids seem to play an important role in the binding of the drug to AT1R, thanks to the formation of extensive networks of hydrogen bonds and salt bridges with the ligand ^[6].

Many drugs used to cure diseases linked with the angiotensin receptor contain a tetrazole group. Studies showed that the tetrazole plays an important role in the binding with AT1R.

 : an important role for AngII binding

Interaction with other GPCRs

It has been showed that AT1Rs were also able to bind with other GPCRs to form homo- or heterodimers. Those interactions can modify the sensitivity of the receptor, which leads to different physiological and pathological conditions than the GPCR monomer ^{[7] [8]}.

Application in the therapeutic field

Since angiotensin receptor is involved in the renin-angiotenisin system, it represents a target of choice to cure some diseases like hypertension or heart failure. An over-stimulation of this receptor seems to be involved in hypertension, coronary artery disease, cardiac hypertrophy, heart failure, arrhythmia, strocke, diabetic nephropathy and ischemic heart and renal diseases ^[9].

Several anti-hypertensive drugs are targeting the angiotensin receptor in order to block it. This is the case for drugs called angiotensin receptor blockers (ARBs) like olmesartan or candesartan. One of the common characteristic they share is their biphenyl-tetrazole scaffold.