Sandbox Reserved 1095: Difference between revisions

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AT1 receptor consists of a 376 amino acid string <ref> [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=4zud&template=main.html Protein Database (PDBsum): 4zud. European Bioinformatics (EBI); 2013.]</ref>. The protein is composed of

<scene name='82/829348/Helix_a/1'>18 α helix</scene>

and <scene name='82/829348/B_sheet/1'>3 β sheets</scene>. Moreover, 7 α helixes are made of a majority of hydrophobic amino acids. These helixes are long enough to cross the membrane and create an <scene name='82/829348/Transmambrane_protein/1'>hydrophobic domain</scene> which is situated into the membrane. The human angiotensin receptor is therefore an α helical trans-membrane protein.

and <scene name='82/829348/B_sheet/1'>3 β sheets</scene>. 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 <scene name='82/829348/Transmambrane_protein/1'>hydrophobic domain</scene> 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 <scene name='82/829348/Disulfuric_bridge/1'>two extracellular disulfure bridges</scene>. This structure is responsible for the opening and the locking of the ligand binding pocket <ref> PMID: 23386604 </ref>. The ligand goes into an <scene name='82/829348/Ligand_blinding_pocket/1'>hydrophilic pocket</scene> created into the membrane thanks to the 7 α helix which creates a gate between the membrane and the extracellular environment.

In the extracellular environment, there is a β-hairpin in conjugation with <scene name='82/829348/Disulfuric_bridge/1'>two extracellular disulfure bridges</scene>. This structure is responsible for the opening and the locking of the ligand binding pocket <ref> PMID: 23386604 </ref>. The ligand goes into a <scene name='82/829348/Ligand_blinding_pocket/1'>hydrophilic pocket</scene> created into the membrane thanks to the 7 α helix which creates a gate between the membrane and the extracellular environment.

=== G protein-binding site ===

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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]] <ref> PMID:30608150 </ref>.

AngII mediates AT1 receptor activation via stacking interactions between Phe8(AngII)/<scene name='82/829348/His_256/2'>His256</scene>(AT1 receptor) and Tyr4(AngII)/<scene name='82/829348/Asn_111/1'>Asn111</scene>(AT1 receptor). This phenomenon results in a conformational change in transmembrane (TM)3-TM6 ~~helices~~ and in interaction between TM2 and TM7.

AngII mediates AT1 receptor activation via stacking interactions between Phe8(AngII)/<scene name='82/829348/His_256/2'>His256</scene>(AT1 receptor) and Tyr4(AngII)/<scene name='82/829348/Asn_111/1'>Asn111</scene>(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 [https://en.wikipedia.org/wiki/Olmesartan Olmesartan] anchored to ATR1 by the residues <scene name='82/829348/Tyr35/6'>Tyr 35</scene>, <scene name='82/829348/Trp84/4'>Trp84</scene> and <scene name='82/829348/Arg167/3'>Arg167</scene>.

The ARB [https://en.wikipedia.org/wiki/Olmesartan Olmesartan] is anchored to ATR1 by the residues <scene name='82/829348/Tyr35/6'>Tyr 35</scene>, <scene name='82/829348/Trp84/4'>Trp84</scene> and <scene name='82/829348/Arg167/3'>Arg167</scene>.

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 <ref name="Zhang2015"/>.

Line 50:

=== Interaction with other GPCRs ===

It has been discovered 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 <ref name="Zhang2015"/> <ref name="Takanobu2017">PMID:28648738 </ref>. The most known heterodimers including AT1 receptor are with [[β2 adrenergic receptor]], [https://en.wikipedia.org/wiki/Apelin_receptor the apelin receptor] ([[5vbl]]), and AT2 receptor. Those interactions could be facilitated by several transmembrane domains.

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 <ref name="Zhang2015"/> <ref name="Takanobu2017">PMID:28648738 </ref>. The most known heterodimers including AT1 receptor are with [[β2 adrenergic receptor]], [https://en.wikipedia.org/wiki/Apelin_receptor the apelin receptor] ([[5vbl]]), and AT2 receptor. Those interactions could be facilitated by several transmembrane domains.

The oligomeric complexes' formation complicate the understanding of AT1R pharmacology.

Line 56:

== Application in the therapeutic field ==

Since angiotensin receptor is involved in the [https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system renin-angiotenisin system], it represents a target of choice to cure some diseases like [https://en.wikipedia.org/wiki/Hypertension hypertension] or [https://en.wikipedia.org/wiki/Heart_failure heart failure].

Since the angiotensin receptor is involved in the [https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system renin-angiotenisin system], it represents a target of choice to cure some diseases like [https://en.wikipedia.org/wiki/Hypertension hypertension] or [https://en.wikipedia.org/wiki/Heart_failure 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 <ref name="Takanobu2017"/>.

Several anti-hypertensive drugs are targeting the angiotensin receptor in order to block it. ~~This~~ kind of drugs are called [https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker angiotensin receptor blockers (ARBs)]. This category ~~include~~ [https://en.wikipedia.org/wiki/Olmesartan olmesartan], [https://en.wikipedia.org/wiki/Candesartan candesartan], and [https://en.wikipedia.org/wiki/Losartan losartan]. One of the common characteristic they share is their biphenyl-tetrazole scaffold.

Several anti-hypertensive drugs are targeting the angiotensin receptor in order to block it. These kind of drugs are called [https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker angiotensin receptor blockers (ARBs)]. This category includes [https://en.wikipedia.org/wiki/Olmesartan olmesartan], [https://en.wikipedia.org/wiki/Candesartan candesartan] and [https://en.wikipedia.org/wiki/Losartan losartan]. One of the common characteristic they share is their biphenyl-tetrazole scaffold.

[[Image:Sartan_drugs.png]]

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@@ Line 28: / Line 28: @@
 AT1 receptor consists of a 376 amino acid string <ref> [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=4zud&template=main.html Protein Database (PDBsum): 4zud. European Bioinformatics (EBI); 2013.]</ref>. The protein is composed of
 <scene name='82/829348/Helix_a/1'>18 α helix</scene>
-and <scene name='82/829348/B_sheet/1'>3 β sheets</scene>. Moreover, 7 α helixes are made of a majority of hydrophobic amino acids. These helixes are long enough to cross the membrane and create an <scene name='82/829348/Transmambrane_protein/1'>hydrophobic domain</scene> which is situated into the membrane. The human angiotensin receptor is therefore an α helical trans-membrane protein.
+and <scene name='82/829348/B_sheet/1'>3 β sheets</scene>. 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 <scene name='82/829348/Transmambrane_protein/1'>hydrophobic domain</scene> 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 <scene name='82/829348/Disulfuric_bridge/1'>two extracellular disulfure bridges</scene>. This structure is responsible for the opening and the locking of the ligand binding pocket <ref> PMID: 23386604  </ref>. The ligand goes into an <scene name='82/829348/Ligand_blinding_pocket/1'>hydrophilic pocket</scene> created into the membrane thanks to the 7 α helix which creates a gate between the membrane and the extracellular environment.
+In the extracellular environment, there is a β-hairpin in conjugation with <scene name='82/829348/Disulfuric_bridge/1'>two extracellular disulfure bridges</scene>. This structure is responsible for the opening and the locking of the ligand binding pocket <ref> PMID: 23386604  </ref>. The ligand goes into a <scene name='82/829348/Ligand_blinding_pocket/1'>hydrophilic pocket</scene> created into the membrane thanks to the 7 α helix which creates a gate between the membrane and the extracellular environment.
 === G protein-binding site ===
@@ Line 38: / Line 38: @@
 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]] <ref> PMID:30608150 </ref>.
-AngII mediates AT1 receptor activation via stacking interactions between Phe8(AngII)/<scene name='82/829348/His_256/2'>His256</scene>(AT1 receptor) and Tyr4(AngII)/<scene name='82/829348/Asn_111/1'>Asn111</scene>(AT1 receptor). This phenomenon results in a conformational change in transmembrane (TM)3-TM6 helices and in interaction between TM2 and TM7.
+AngII mediates AT1 receptor activation via stacking interactions between Phe8(AngII)/<scene name='82/829348/His_256/2'>His256</scene>(AT1 receptor) and Tyr4(AngII)/<scene name='82/829348/Asn_111/1'>Asn111</scene>(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 [https://en.wikipedia.org/wiki/Olmesartan Olmesartan] anchored to ATR1 by the residues <scene name='82/829348/Tyr35/6'>Tyr 35</scene>, <scene name='82/829348/Trp84/4'>Trp84</scene> and <scene name='82/829348/Arg167/3'>Arg167</scene>.
+The ARB [https://en.wikipedia.org/wiki/Olmesartan Olmesartan] is anchored to ATR1 by the residues <scene name='82/829348/Tyr35/6'>Tyr 35</scene>, <scene name='82/829348/Trp84/4'>Trp84</scene> and <scene name='82/829348/Arg167/3'>Arg167</scene>.
 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 <ref name="Zhang2015"/>.
@@ Line 50: / Line 50: @@
 === Interaction with other GPCRs ===
-It has been discovered 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 <ref name="Zhang2015"/> <ref name="Takanobu2017">PMID:28648738 </ref>. The most known heterodimers including AT1 receptor are with [[β2 adrenergic receptor]], [https://en.wikipedia.org/wiki/Apelin_receptor the apelin receptor] ([[5vbl]]), and AT2 receptor. Those interactions could be facilitated by several transmembrane domains.
+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 <ref name="Zhang2015"/> <ref name="Takanobu2017">PMID:28648738 </ref>. The most known heterodimers including AT1 receptor are with [[β2 adrenergic receptor]], [https://en.wikipedia.org/wiki/Apelin_receptor the apelin receptor] ([[5vbl]]), and AT2 receptor. Those interactions could be facilitated by several transmembrane domains.
 The oligomeric complexes' formation complicate the understanding of AT1R pharmacology.
@@ Line 56: / Line 56: @@
 == Application in the therapeutic field ==
-Since angiotensin receptor is involved in the [https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system renin-angiotenisin system], it represents a target of choice to cure some diseases like [https://en.wikipedia.org/wiki/Hypertension hypertension] or [https://en.wikipedia.org/wiki/Heart_failure heart failure].
+Since the angiotensin receptor is involved in the [https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system renin-angiotenisin system], it represents a target of choice to cure some diseases like [https://en.wikipedia.org/wiki/Hypertension hypertension] or [https://en.wikipedia.org/wiki/Heart_failure 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  <ref name="Takanobu2017"/>.
-Several anti-hypertensive drugs are targeting the angiotensin receptor in order to block it. This kind of drugs are called [https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker angiotensin receptor blockers (ARBs)]. This category include [https://en.wikipedia.org/wiki/Olmesartan olmesartan], [https://en.wikipedia.org/wiki/Candesartan candesartan], and [https://en.wikipedia.org/wiki/Losartan losartan]. One of the common characteristic they share is their biphenyl-tetrazole scaffold.
+Several anti-hypertensive drugs are targeting the angiotensin receptor in order to block it. These kind of drugs are called [https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker angiotensin receptor blockers (ARBs)]. This category includes [https://en.wikipedia.org/wiki/Olmesartan olmesartan], [https://en.wikipedia.org/wiki/Candesartan candesartan] and [https://en.wikipedia.org/wiki/Losartan losartan]. One of the common characteristic they share is their biphenyl-tetrazole scaffold.
 [[Image:Sartan_drugs.png]]