Sandbox Reserved 1095: Difference between revisions
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=== Recent studies === | === Recent studies === | ||
Finally, around 2015, researchers have found the crystal structure of the receptor in complex with its antagonist [https://pubchem.ncbi.nlm.nih.gov/compound/ZD-7155-hydrochloride ZD7155] and with an inverse agonist [https://en.wikipedia.org/wiki/Olmesartan olmesartan]<ref> PMID: 26420482 </ref>. [https://en.wikipedia.org/wiki/X-ray_crystallography X-ray cryogenic-crystallography] has been used. They have 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. | Finally, around 2015, researchers have found the crystal structure of the receptor in complex with its antagonist [https://pubchem.ncbi.nlm.nih.gov/compound/ZD-7155-hydrochloride ZD7155] and with an inverse agonist [https://en.wikipedia.org/wiki/Olmesartan olmesartan]<ref> PMID: 26420482 </ref>. [https://en.wikipedia.org/wiki/X-ray_crystallography X-ray cryogenic-crystallography] has been used. They have 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 have also been solved in 2017 using an other method called serial femtosecond crystallography, corresponding to the structure [http://proteopedia.org/wiki/index.php/4yay 4YAY] <ref name="Zhang2017"> | The structure of this protein have also been solved in 2017 using an other method called serial femtosecond crystallography, corresponding to the structure [http://proteopedia.org/wiki/index.php/4yay 4YAY] <ref name="Zhang2017">PMID:25913193</ref>. | ||
== Structure (function relationship) == | == Structure (function relationship) == | ||
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=== G protein-binding site === | === 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]] <ref> | 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>. | ||
=== Interaction with drugs === | === Interaction with drugs === | ||
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=== Interaction with other GPCRs === | === 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"> | 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 [[Beta-2 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. | The oligomeric complexes' formation complicate the understanding of AT1R pharmacology. | ||
