Sandbox Reserved 1722: Difference between revisions
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==== Agonists ==== | ==== Agonists ==== | ||
[[Image:Agoniststogether.PNG |400px|right|thumb|'''Figure 4''': Structure of MRGPRX2 Agonists. (A) Structure of R-Zinc 3573. A cationic ligand selected for binding to MRGPRX2 <ref name="Yang">Yang, Fan, et al. "Structure, function and pharmacology of human itch receptor complexes." Nature, Nature Publishing Group, 17 November 2021, https://www.nature.com/articles/s41586-021-04077-y</ref>.(B) Structure of Cortistatin-14 with resolved amino acids highlighted in green. These ligands were used as a probes for MRGPRX2 function and stabilization for structure determination <ref name="Yang">Yang, Fan, et al. "Structure, function and pharmacology of human itch receptor complexes." Nature, Nature Publishing Group, 17 November 2021, https://www.nature.com/articles/s41586-021-04077-y</ref>.]] | [[Image:Agoniststogether.PNG |400px|right|thumb|'''Figure 4''': Structure of MRGPRX2 Agonists. (A) Structure of R-Zinc 3573. A cationic ligand selected for binding to MRGPRX2 <ref name="Yang">Yang, Fan, et al. "Structure, function and pharmacology of human itch receptor complexes." Nature, Nature Publishing Group, 17 November 2021, https://www.nature.com/articles/s41586-021-04077-y</ref>. (B) Structure of Cortistatin-14 with resolved amino acids highlighted in green. These ligands were used as a probes for MRGPRX2 function and stabilization for structure determination <ref name="Yang">Yang, Fan, et al. "Structure, function and pharmacology of human itch receptor complexes." Nature, Nature Publishing Group, 17 November 2021, https://www.nature.com/articles/s41586-021-04077-y</ref>.]] | ||
===== Small Molecule ===== | ===== Small Molecule ===== | ||
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== Clinical Relevance == | == Clinical Relevance == | ||
[[Image:Zinc_and_drugs_snip.PNG|450px|right|thumb|'''Figure 6''': Structures of (R)-Zinc-3573, Dextromethorphan, Morphine, and Codeine. The blue circles indicate conserved basic N-dimethyl group and the green squares show the conserved benzene rings | [[Image:Zinc_and_drugs_snip.PNG|450px|right|thumb|'''Figure 6''': Structures of (R)-Zinc-3573, Dextromethorphan, Morphine, and Codeine. The blue circles indicate conserved basic N-dimethyl group and the green squares show the conserved benzene rings <ref name="Cao"/>.]] | ||
MRGPRX2 activation is associated with chronic itching or anaphylaxis reactions, a common side effect of many prescribed medications <ref name="Cao"/>. Among these drugs are opioids [https://en.wikipedia.org/wiki/Morphine morphine] and [https://en.wikipedia.org/wiki/Codeine codeine] and [https://en.wikipedia.org/wiki/Dextromethorphan dextromethorphan]. By analyzing the structures of these drugs, it can be seen that they contain chemical features similar to <scene name='90/904328/Zizwithaa/5'>agonist R-Zinc-3573</scene> (see Figure 6). They contain a conserved benzene ring that stabilizes them in binding pocket 1. Similarly, they contain an N-dimethyl group that would allow them to form key ionic bonds with residues Asp-184 and Glu-164. Lastly, these drugs have a similar shape and size to that of the agonist R-Zinc-3573 <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> (see Figure 6). These structural and chemical similarities indicate the possibility of a similar binding mechanism to previously discussed agonist, (R)-Zinc-3573. | MRGPRX2 activation is associated with chronic itching or anaphylaxis reactions, a common side effect of many prescribed medications <ref name="Cao"/>. Among these drugs are opioids [https://en.wikipedia.org/wiki/Morphine morphine] and [https://en.wikipedia.org/wiki/Codeine codeine] and [https://en.wikipedia.org/wiki/Dextromethorphan dextromethorphan]. By analyzing the structures of these drugs, it can be seen that they contain chemical features similar to <scene name='90/904328/Zizwithaa/5'>agonist R-Zinc-3573</scene> (see Figure 6). They contain a conserved benzene ring that stabilizes them in binding pocket 1. Similarly, they contain an N-dimethyl group that would allow them to form key ionic bonds with residues Asp-184 and Glu-164. Lastly, these drugs have a similar shape and size to that of the agonist R-Zinc-3573 <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> (see Figure 6). These structural and chemical similarities indicate the possibility of a similar binding mechanism to previously discussed agonist, (R)-Zinc-3573. | ||
