Sandbox Reserved 1095

This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115.

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Human Angiotensin Receptor in complex with olmesartan (4ZUD)

Angiotensin receptors of type 1 belong to the G protein coupled receptor (GPCR) family. These transmembrane proteins interact with angiotensin II, their ligand, and play a crucial role in the renin-angiotensin-aldosterone system. AT1 receptors are predominantly expressed in cardiovascular tissues including heart, endothelium, kidney, vascular smooth muscle cells as well as lungs, brain and adrenal cortex. They are therefore important for the cardiovascular physiology.

spinqualitylabelsall models Human angiotensin receptor Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Functions The AT1 receptors participate to the regulation of the renin-angiotensin-aldosterone system and therefore to the regulation of the cardiovascular system. It is crucial for the maintenance of blood pressure, electrolyte homeostasis, water balance, hormone secretion and renal functions. AT1 receptors interact with angiotensin II and are therefore responsible for the triggering of intracellular signal transduction cascades mediating most functions of Angiotensin II, such as vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and renal functions. When activated by the binding of angiotensin II, AT1R initiates a vascular remodeling activity. By its coupling with the G proteins, Gq and Gi of the Gαq/11 subtype, the intracellular signal transduction is initiated. During these transduction cascades, a large variety of protein kinases are activated. Among them are : mitogen-activated protein kinase (MAPK) family, extracellular signal regulated kinase (ERK) and c-Jun N terminal kinase (JNK). The complex functioning of AT1 receptor signaling involve crosstalk with other signaling cascades too. History Discovery of angiotensin receptors Researchers had suspicions since the 1970s about the existence of different angiotensin receptors. However, tools to identify those distinct trans-membrane receptors became available only a decade later. Receptors binding assays identified angiotensin receptors in vitro using radioactive angiotensin. Results showed several types of angiotensin receptors, found in different tissues. The main receptors are AT1 and AT2 . Nomenclature Three labs discovered in the same time these two angiotensin receptors and proposed their own nomenclature, leading to confusion. To avoid this, a group of researchers met in Baltimore in 1991 to define a coherent nomenclature. Under the presidency of Merlin Bumpus, a common ground has been found and angiotensin receptors have been classified into two groups called AT1 and AT2 receptors . Recent studies Around 2015, researchers found the crystal structure of the receptor in complex with its antagonist ZD7155 and with an inverse agonist olmesartan. X-ray cryogenic-crystallography has been used. They found similar conformation of the receptor when it is linked to the antagonist or to the inverse agonist. They have also found conserved molecular recognition modes. To complete this, they have performed mutagenesis experiments and managed to identify several residues in interaction with the ligand. The structure of this protein was solved in 2017 using another method called serial femtosecond crystallography, corresponding to the structure 4YAY . Structure Primary and secondary structure The human AT1 receptor consists of a 376 amino acid string . The protein is composed of 18 α helixes and 3 β sheets. Moreover, 7 α helixes are made of a majority of hydrophobic amino acids. These helixes are long enough to cross the membrane and create a hydrophobic domain which is situated into the membrane. The human angiotensin receptor is therefore an α helical trans-membrane protein. Since the angiotensin receptor belongs to the GPCRs family, those 7 α helixes contain 3 extracellular and 3 intracellular loops. The N terminus corresponds to the extracellular domain. The C terminal domain is located intracellularly. Ligand binding pocket In the extracellular environment, there is a β-hairpin in conjugation with two extracellular disulfure bridges. This structure is responsible for the opening and the locking of the ligand binding pocket . The ligand goes into a hydrophilic pocket created into the membrane thanks to the 7 α helixes which creates a gate between the membrane and the extracellular environment. G protein-binding site When the angiotensin II binds to the angiotensin receptor in the ligand binding pocket, the conformation of the trans-membrane domain changes to create a cytosolic cleft for the binding and activation of G proteins. In this cleft, several conserved residues can be found, which form functional motifs present in all GPCRs . AngII mediates AT1 receptor activation via stacking interactions between Phe8(AngII)/His256(AT1 receptor) and Tyr4(AngII)/Asn111(AT1 receptor). This phenomenon results in a conformational change in transmembrane (TM)3-TM6 helixes and in interaction between TM2 and TM7 . Interaction with drugs Angiotensin Receptor Blockers (ARBs) are used to cure diseases linked to AT1R. The ARB olmesartan is anchored to ATR1 by the residues Tyr35, Trp84 and Arg167. Those three 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 . Many ARBs contain a tetrazole group. Studies showed that tetrazole plays an important role in the binding with AT1R. Interaction with other GPCRs It has been discovered that AT1Rs were also able to bind with other GPCRs to form homo- or hetero-dimers. Those interactions can modify the sensitivity of the receptor, which leads to different physiological and pathological conditions than the GPCR monomer . The most known heterodimers including AT1 receptor are with Beta-2 Adrenergic Receptor, the apelin receptor (5vbl), and AT2 receptor. Those interactions could be facilitated by several transmembrane domains. This oligomeric complexes' formation complicate the understanding of AT1R pharmacology. Application in the therapeutic field Since the 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, stroke, diabetic nephropathy and ischemic heart and renal diseases . Several anti-hypertensive drugs are targeting the angiotensin receptor in order to block it. These kind of drugs are called angiotensin receptor blockers (ARBs). This category includes olmesartan, candesartan and losartan. One of the common characteristic they share is their biphenyl-tetrazole scaffold.