Sandbox Reserved 1723: Difference between revisions

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

In β2AR, and other Class A GPCRs, a “toggle switch” of <scene name='90/904327/B2artoggleswitchyes/5'>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_2/2'>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'' ====

In common Class A GPCRs the disulfide bond associated with the initiation of signal transduction is located on the extracellular domain of the 7 transmembrane helices. <ref name="Zhang">PMID: 26467290</ref> The <scene name='90/904328/B2ardisulfidebond1_pt_3/1'>disulfide bond of β2AR</scene>, a well studied Class A GPCR, occurs between transmembrane three (TM3) C106 and extracellular loop (EL) C191. This loop crosses through the middle of the extracellular domain, creating a barrier for bulkier substrates. The <scene name='90/~~904328~~/7tm_domain_pt_6/1'> ~~MRGPRX2~~ disulfide bond</scene> is located between (TM4) C168 and (TM5) C180. This is a TM to TM disulfide bond as compared to a TM to EL disulfide bond seen in typical Class A GPCRs. This lack of interaction with the extracellular loop seen in MRGPRX2 causes the extracellular loop to flip on top of the TM4 and TM5 resulting in an open space for larger substrates to be able to interact with the receptor.

In common Class A GPCRs the disulfide bond associated with the initiation of signal transduction is located on the extracellular domain of the 7 transmembrane helices. <ref name="Zhang">PMID: 26467290</ref> The <scene name='90/904328/B2ardisulfidebond1_pt_3/1'>disulfide bond of β2AR</scene>, a well studied Class A GPCR, occurs between transmembrane three (TM3) C106 and extracellular loop (EL) C191. This loop crosses through the middle of the extracellular domain, creating a barrier for bulkier substrates. The <scene name='90/904327/7tm_domain_pt_6/1'>disulfide bond of MRGPRX2</scene> is located between (TM4) C168 and (TM5) C180. This is a TM to TM disulfide bond as compared to a TM to EL disulfide bond seen in typical Class A GPCRs. This lack of interaction with the extracellular loop seen in MRGPRX2 causes the extracellular loop to flip on top of the TM4 and TM5 resulting in an open space for larger substrates to be able to interact with the receptor.

==== ''PIF Motif'' ====

MRGPRX2 also differs from typical Class A GPCRs based on substitutions in the PIF/connector motif, which acts as a microswitch. PIF plays a role in connecting the binding pocket to conformational rearrangements required for receptor activation<ref name="Schonegge">Schonegge, Anne-Marie, et al. "Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity." Nature, Nature Publishing Group, 18 December 2017, https://www.nature.com/articles/s41467-017-02257-x</ref>. The PIF motif is located towards the base of the TM domains. In a Class A ~~GPCRs~~, the <scene name='90/~~904328~~/B2arpif_pt_2/1'> ~~β2AR~~ PIF motif</scene> consists of Phe-211, Ile-121, and Phe-282 on TM domains 5, 3, and 6, respectively. However, for MRGPRX2, this <scene name='90/904328/Mxpifnolabel_pt_3/1'>motif</scene> is replaced with Leu-194 on TM5, Leu-117 on TM3, and Phe-232 on TM6.

MRGPRX2 also differs from typical Class A GPCRs based on substitutions in the PIF/connector motif, which acts as a microswitch. PIF plays a role in connecting the binding pocket to conformational rearrangements required for receptor activation<ref name="Schonegge">Schonegge, Anne-Marie, et al. "Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity." Nature, Nature Publishing Group, 18 December 2017, https://www.nature.com/articles/s41467-017-02257-x</ref>. The PIF motif is located towards the base of the TM domains. In a Class A GPCR, like β2AR, the <scene name='90/904327/B2arpif_pt_2/1'>PIF motif</scene> consists of Phe-211, Ile-121, and Phe-282 on TM domains 5, 3, and 6, respectively. However, for MRGPRX2, this <scene name='90/904328/Mxpifnolabel_pt_3/1'>motif</scene> is replaced with Leu-194 on TM5, Leu-117 on TM3, and Phe-232 on TM6.

==== ''DRY Motif'' ====

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@@ Line 22: / Line 22: @@
 ==== ''Toggle Switch'' ====
-In β2AR, and other Class A GPCRs, a “toggle switch” of <scene name='90/904327/B2artoggleswitchyes/5'>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_2/2'>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'' ====
-In common Class A GPCRs the disulfide bond associated with the initiation of signal transduction is located on the extracellular domain of the 7 transmembrane helices. <ref name="Zhang">PMID: 26467290</ref> The <scene name='90/904328/B2ardisulfidebond1_pt_3/1'>disulfide bond of β2AR</scene>, a well studied Class A GPCR, occurs between transmembrane three (TM3) C106 and extracellular loop (EL) C191. This loop crosses through the middle of the extracellular domain, creating a barrier for bulkier substrates. The <scene name='90/904328/7tm_domain_pt_6/1'> MRGPRX2 disulfide bond</scene> is located between (TM4) C168 and (TM5) C180. This is a TM to TM disulfide bond as compared to a TM to EL disulfide bond seen in typical Class A GPCRs. This lack of interaction with the extracellular loop seen in MRGPRX2 causes the extracellular loop to flip on top of the TM4 and TM5 resulting in an open space for larger substrates to be able to interact with the receptor.
+In common Class A GPCRs the disulfide bond associated with the initiation of signal transduction is located on the extracellular domain of the 7 transmembrane helices. <ref name="Zhang">PMID: 26467290</ref> The <scene name='90/904328/B2ardisulfidebond1_pt_3/1'>disulfide bond of β2AR</scene>, a well studied Class A GPCR, occurs between transmembrane three (TM3) C106 and extracellular loop (EL) C191. This loop crosses through the middle of the extracellular domain, creating a barrier for bulkier substrates. The <scene name='90/904327/7tm_domain_pt_6/1'>disulfide bond of MRGPRX2</scene> is located between (TM4) C168 and (TM5) C180. This is a TM to TM disulfide bond as compared to a TM to EL disulfide bond seen in typical Class A GPCRs. This lack of interaction with the extracellular loop seen in MRGPRX2 causes the extracellular loop to flip on top of the TM4 and TM5 resulting in an open space for larger substrates to be able to interact with the receptor.
 ==== ''PIF Motif'' ====
-MRGPRX2 also differs from typical Class A GPCRs based on substitutions in the PIF/connector motif, which acts as a microswitch. PIF plays a role in connecting the binding pocket to conformational rearrangements required for receptor activation<ref name="Schonegge">Schonegge, Anne-Marie, et al. "Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity." Nature, Nature Publishing Group, 18 December 2017, https://www.nature.com/articles/s41467-017-02257-x</ref>. The PIF motif is located towards the base of the TM domains. In a Class A GPCRs, the <scene name='90/904328/B2arpif_pt_2/1'> β2AR PIF motif</scene> consists of Phe-211, Ile-121, and Phe-282 on TM domains 5, 3, and 6, respectively. However, for MRGPRX2, this <scene name='90/904328/Mxpifnolabel_pt_3/1'>motif</scene> is replaced with Leu-194 on TM5, Leu-117 on TM3, and Phe-232 on TM6.
+MRGPRX2 also differs from typical Class A GPCRs based on substitutions in the PIF/connector motif, which acts as a microswitch. PIF plays a role in connecting the binding pocket to conformational rearrangements required for receptor activation<ref name="Schonegge">Schonegge, Anne-Marie, et al. "Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity." Nature, Nature Publishing Group, 18 December 2017, https://www.nature.com/articles/s41467-017-02257-x</ref>. The PIF motif is located towards the base of the TM domains. In a Class A GPCR, like β2AR, the <scene name='90/904327/B2arpif_pt_2/1'>PIF motif</scene> consists of Phe-211, Ile-121, and Phe-282 on TM domains 5, 3, and 6, respectively. However, for MRGPRX2, this <scene name='90/904328/Mxpifnolabel_pt_3/1'>motif</scene> is replaced with Leu-194 on TM5, Leu-117 on TM3, and Phe-232 on TM6.
 ==== ''DRY Motif'' ====