Sandbox Reserved 1722: Difference between revisions

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~~[[Image:Newmembrane.PNG|350px|right|thumb|'''Figure 1''': MRGPRX2 in the cellular membrane. <ref name="Cao"/>]]~~

== G-Protein Coupled Receptors ==

[[Image:Newmembrane.PNG|400px|right|thumb|'''Figure 1''': MRGPRX2 in the cellular membrane. <ref name="Cao"/>]][https://proteopedia.org/wiki/index.php/G_protein-coupled_receptors G-protein coupled receptors](GCPRs) are a large family of cell surface membrane receptors. Once bound to a wide variety of extracellular ligands, GCPRs undergo a conformational change and relay information to intracellular secondary messengers <ref name="Thal">Thal, David M., et al. "Structural insights into G-protein-coupled receptor allostery." Nature, Nature Publishing Group, 04 July 2018, https://www.nature.com/articles/s41586-018-0259-z</ref>. This G protein activation results in a cellular response dependent on the ligand bound and location of the GPCR in the body. GCPRs can be broken down into five families: the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin family (class A)], the [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin family (class B)], the [https://en.wikipedia.org/wiki/Adhesion_G_protein-coupled_receptor adhesion family], the [https://en.wikipedia.org/wiki/Class_C_GPCR glutamate family (class C)], and the [https://en.wikipedia.org/wiki/Frizzled frizzled/taste family (class F)] <ref name="Zhang">PMID: 26467290</ref>. All of the families have a similar transmembrane (TM) domain consisting of seven <scene name='90/904328/7tm_domain_pt_3/7'> 7 α-helices</scene> complexed with intracellular G proteins (Figure 1).

[https://proteopedia.org/wiki/index.php/G_protein-coupled_receptors G-protein coupled receptors](GCPRs) are a large family of cell surface membrane receptors. Once bound to a wide variety of extracellular ligands, GCPRs undergo a conformational change and relay information to intracellular secondary messengers <ref name="Thal">Thal, David M., et al. "Structural insights into G-protein-coupled receptor allostery." Nature, Nature Publishing Group, 04 July 2018, https://www.nature.com/articles/s41586-018-0259-z</ref>. This G protein activation results in a cellular response dependent on the ligand bound and location of the GPCR in the body. GCPRs can be broken down into five families: the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin family (class A)], the [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin family (class B)], the [https://en.wikipedia.org/wiki/Adhesion_G_protein-coupled_receptor adhesion family], the [https://en.wikipedia.org/wiki/Class_C_GPCR glutamate family (class C)], and the [https://en.wikipedia.org/wiki/Frizzled frizzled/taste family (class F)] <ref name="Zhang">PMID: 26467290</ref>. All of the families have a similar transmembrane (TM) domain consisting of seven <scene name='90/904328/7tm_domain_pt_3/7'> 7 α-helices</scene> complexed with intracellular G proteins (Figure 1).

=== Class A GCPRs ===

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==== ''Toggle Switch'' ====

In β2AR, and other Class A GPCRs, a “toggle switch” of <scene name='90/904327/B2artoggleswitchyes/7'>Trp-286</scene> which limits the proximity of the TM helices as tryptophan sterically occludes tight interaction. This results in a deep binding pocket for ligand binding. In contrast, in MRGPRX2 Trp-286 is replaced by <scene name='90/~~904328~~/Toggle_switch_gly_pt_2/1'>Gly-236</scene> <ref name="Cao"/> <ref name="Yang"/>. Glycine is a much smaller amino acid and thus allows the helices to close the base of the binding pocket. This causes MRGPRX2 to have a much shallower binding site and allows more promiscuous ligand binding. This can be seen in a shorter distance from the toggle switch to the ligand in β2AR compared to MRGPRX2.

In β2AR, and other Class A GPCRs, a “toggle switch” of <scene name='90/904327/B2artoggleswitchyes/7'>Trp-286</scene> which limits the proximity of the TM helices as tryptophan sterically occludes tight interaction. This results in a deep binding pocket for ligand binding. In contrast, in MRGPRX2 Trp-286 is replaced by <scene name='90/904327/Toggle_switch_gly_pt_2/1'>Gly-236</scene> <ref name="Cao"/> <ref name="Yang"/>. Glycine is a much smaller amino acid and thus allows the helices to close the base of the binding pocket. This causes MRGPRX2 to have a much shallower binding site and allows more promiscuous ligand binding. This can be seen in a shorter distance from the toggle switch to the ligand in β2AR compared to MRGPRX2.

==== ''Disulfide bonds'' ====

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@@ Line 4: / Line 4: @@
 <StructureSection load='' size='350' frame='true' side='right' caption='Structure of MRGPRX2 with transmembrane helices shown in blue, Gαq shown in purple, Gβ1 shown in yellow, and Gγ2 shown in pink (PDB entry [https://www.rcsb.org/structure/7S8L 7S8L])' scene='90/904327/Overviewfrontpage/1'>
-[[Image:Newmembrane.PNG|350px|right|thumb|'''Figure 1''': MRGPRX2 in the cellular membrane. <ref name="Cao"/>]]
 == G-Protein Coupled Receptors ==
+[[Image:Newmembrane.PNG|400px|right|thumb|'''Figure 1''': MRGPRX2 in the cellular membrane. <ref name="Cao"/>]][https://proteopedia.org/wiki/index.php/G_protein-coupled_receptors G-protein coupled receptors](GCPRs) are a large family of cell surface membrane receptors. Once bound to a wide variety of extracellular ligands, GCPRs undergo a conformational change and relay information to intracellular secondary messengers <ref name="Thal">Thal, David M., et al. "Structural insights into G-protein-coupled receptor allostery." Nature, Nature Publishing Group, 04 July 2018, https://www.nature.com/articles/s41586-018-0259-z</ref>. This G protein activation results in a cellular response dependent on the ligand bound and location of the GPCR in the body. GCPRs can be broken down into five families: the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin family (class A)], the [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin family (class B)], the [https://en.wikipedia.org/wiki/Adhesion_G_protein-coupled_receptor adhesion family], the [https://en.wikipedia.org/wiki/Class_C_GPCR glutamate family (class C)], and the [https://en.wikipedia.org/wiki/Frizzled frizzled/taste family (class F)] <ref name="Zhang">PMID: 26467290</ref>. All of the families have a similar transmembrane (TM) domain consisting of seven <scene name='90/904328/7tm_domain_pt_3/7'> 7 α-helices</scene> complexed with intracellular G proteins (Figure 1).
-[https://proteopedia.org/wiki/index.php/G_protein-coupled_receptors G-protein coupled receptors](GCPRs) are a large family of cell surface membrane receptors. Once bound to a wide variety of extracellular ligands, GCPRs undergo a conformational change and relay information to intracellular secondary messengers <ref name="Thal">Thal, David M., et al. "Structural insights into G-protein-coupled receptor allostery." Nature, Nature Publishing Group, 04 July 2018, https://www.nature.com/articles/s41586-018-0259-z</ref>. This G protein activation results in a cellular response dependent on the ligand bound and location of the GPCR in the body. GCPRs can be broken down into five families: the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin family (class A)], the [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin family (class B)], the [https://en.wikipedia.org/wiki/Adhesion_G_protein-coupled_receptor adhesion family], the [https://en.wikipedia.org/wiki/Class_C_GPCR glutamate family (class C)], and the [https://en.wikipedia.org/wiki/Frizzled frizzled/taste family (class F)] <ref name="Zhang">PMID: 26467290</ref>. All of the families have a similar transmembrane (TM) domain consisting of seven <scene name='90/904328/7tm_domain_pt_3/7'> 7 α-helices</scene> complexed with intracellular G proteins (Figure 1).
 === Class A GCPRs ===
@@ Line 22: / Line 20: @@
 ==== ''Toggle Switch'' ====
-In β2AR, and other Class A GPCRs, a “toggle switch” of <scene name='90/904327/B2artoggleswitchyes/7'>Trp-286</scene> which limits the proximity of the TM helices as tryptophan sterically occludes tight interaction. This results in a deep binding pocket for ligand binding. In contrast, in MRGPRX2 Trp-286 is replaced by <scene name='90/904328/Toggle_switch_gly_pt_2/1'>Gly-236</scene> <ref name="Cao"/> <ref name="Yang"/>. Glycine is a much smaller amino acid and thus allows the helices to close the base of the binding pocket. This causes MRGPRX2 to have a much shallower binding site and allows more promiscuous ligand binding. This can be seen in a shorter distance from the toggle switch to the ligand in β2AR compared to MRGPRX2.
+In β2AR, and other Class A GPCRs, a “toggle switch” of <scene name='90/904327/B2artoggleswitchyes/7'>Trp-286</scene> which limits the proximity of the TM helices as tryptophan sterically occludes tight interaction. This results in a deep binding pocket for ligand binding. In contrast, in MRGPRX2 Trp-286 is replaced by <scene name='90/904327/Toggle_switch_gly_pt_2/1'>Gly-236</scene> <ref name="Cao"/> <ref name="Yang"/>. Glycine is a much smaller amino acid and thus allows the helices to close the base of the binding pocket. This causes MRGPRX2 to have a much shallower binding site and allows more promiscuous ligand binding. This can be seen in a shorter distance from the toggle switch to the ligand in β2AR compared to MRGPRX2.
 ==== ''Disulfide bonds'' ====