Sandbox Reserved 1722: Difference between revisions
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===== ''DRY Motif'' ===== | ===== ''DRY Motif'' ===== | ||
The DRY motif is a proton microswitch that is located near the G-protein binding site C-terminal on TM3 <ref name="Schonegge"/>. It acts as an ion lock when the GPCR is not being activated, preventing unnecessary activation of the G-proteins <ref name="Zhou"/>. This motif is conserved in typical Class A GPCRS however, in MRGPRX2 it is only partially conserved. The arginine is conserved, while the aspartate is replaced by a glutamate and the tyrosine is replaced by a cysteine <ref name="Yang"/> <ref name="Sandoval">Sandoval, A., et al. "The Molecular Switching Mechanism at the Conserved D(E)RY Motif in Class-A GPCRs." Biophysical journal, 111(1), 79-89. https://doi.org/10.1016/j.bpj.2016.06.004 </ref>. | The DRY motif is a proton microswitch that is located near the G-protein binding site C-terminal on TM3 <ref name="Schonegge"/>. It acts as an ion lock when the GPCR is not being activated, preventing unnecessary activation of the G-proteins <ref name="Zhou"/>. This motif is conserved in typical Class A GPCRS however, in MRGPRX2 it is only partially conserved. The arginine is conserved, while the aspartate is replaced by a glutamate and the tyrosine is replaced by a cysteine <ref name="Yang"/> <ref name="Sandoval">Sandoval, A., et al. "The Molecular Switching Mechanism at the Conserved D(E)RY Motif in Class-A GPCRs." Biophysical journal, 111(1), 79-89. https://doi.org/10.1016/j.bpj.2016.06.004 </ref>. The replacement of tyrosine for cysteine results in the helices coming closer together, creating a shallower binding pocket.<ref name="Zhou"/> | ||
===== ''Sodium Binding'' ===== | ===== ''Sodium Binding'' ===== | ||
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[[Image: Drugs.PNG|400px|right|thumb|'''Figure 4''': Structures of Dextromethorphan, Morphine, and Codeine.<ref name="Cao"/>]] | [[Image: Drugs.PNG|400px|right|thumb|'''Figure 4''': Structures of Dextromethorphan, Morphine, and Codeine.<ref name="Cao"/>]] | ||
Many drugs activate MRGPRX2 as a side effect that causes the sensation of itchiness <ref name="Cao"/>. Among these drugs are morphine, codeine, and dextromethorphan.These drugs contain similar chemical features that are also found in (R)- ZINC-3573, introducing the idea of a similar binding mechanism <ref name="Babina"> Babina, M., et al. "MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway." Journal of Investigative Dermatology, 141(6), 1286-1296. https://doi.org/10.1016/j.jid.2020.09.017</ref>. | Many drugs activate MRGPRX2 as a side effect that causes the sensation of itchiness <ref name="Cao"/>. Among these drugs are morphine, codeine, and dextromethorphan. These drugs contain similar chemical features that are also found in (R)- ZINC-3573, introducing the idea of a similar binding mechanism <ref name="Babina"> Babina, M., et al. "MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway." Journal of Investigative Dermatology, 141(6), 1286-1296. https://doi.org/10.1016/j.jid.2020.09.017</ref>. | ||
Due to mutations in key structural features of typical Class A GPCRS, MRGPRX2, it is able to bind to a variety of substrates that then mediate the signaling pathway for the sensation of itching. | Due to mutations in key structural features of typical Class A GPCRS, MRGPRX2, it is able to bind to a variety of substrates that then mediate the signaling pathway for the sensation of itching. | ||
