Sandbox Reserved 1722: Difference between revisions

Line 56:

===== Small Molecule =====

<scene name='90/904328/Zinc/4'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2 (Figure 4A). Its N-dimethyl is inserted into subpocket 1 of the binding cavity with aromatic amino acid residues Phe-170, Trp-243, and Phe-244. In this <scene name='90/904328/Zizwithaa/5'>cavity</scene>, N-dimethyl group on the ligand makes ion pairs with Asp-184 and Glu-164. The ligand is then stabilized by stacking its ring with Trp-248 and the Cys-168 to Cys-180 disulfide bond <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>.

<scene name='90/904328/Zinc/4'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2 (Figure 4A). Its N-dimethyl is inserted into subpocket 1 of the binding cavity with aromatic amino acid residues Phe-170, Trp-243, and Phe-244. In this <scene name='90/904328/Zizwithaa/6'>cavity</scene>, N-dimethyl group on the ligand makes ion pairs with Asp-184 and Glu-164. The ligand is then stabilized by stacking its ring with Trp-248 and the Cys-168 to Cys-180 disulfide bond <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>.

===== Peptide =====

Line 77:

[[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/6'>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.

This receptor is shallow and is able to bind to a variety of drugs, creating a need for a solution to mediate the effects of MRGPRX2 activation. Currently, there is research for the development of small antagonists that will induce an anti-inflammatory effect by preventing [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE-dependent] mast cell degranulation <ref name="McNeil">McNeil, B. D., et al. "MRGPRX2 and Adverse Drug Reactions." Frontier Immunology, 06 August 2021, https://www.frontiersin.org/articles/10.3389/fimmu.2021.676354/full</ref>. There are two antagonists that have been adapted from being antagonists to another Class A GPCR, [https://en.wikipedia.org/wiki/NK1_receptor_antagonist neurokinin-1 receptor (NK-1R)] <ref name="Ogasawara">Ogasawara, H., et al. "Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells." Journal of Leukocyte Biology, 12 July 2019, https://jlb.onlinelibrary.wiley.com/doi/10.1002/JLB.2AB1018-405R</ref>. Through the development of this research, these adverse side effects can be relieved and improve patient satisfaction.

Sandbox Reserved 1722: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 56: / Line 56: @@
 ===== Small Molecule =====
-<scene name='90/904328/Zinc/4'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2 (Figure 4A). Its N-dimethyl is inserted into subpocket 1 of the binding cavity with aromatic amino acid residues Phe-170, Trp-243, and Phe-244. In this <scene name='90/904328/Zizwithaa/5'>cavity</scene>, N-dimethyl group on the ligand makes ion pairs with Asp-184 and Glu-164. The ligand is then stabilized by stacking its ring with Trp-248 and the Cys-168 to Cys-180 disulfide bond <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>.
+<scene name='90/904328/Zinc/4'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2 (Figure 4A). Its N-dimethyl is inserted into subpocket 1 of the binding cavity with aromatic amino acid residues Phe-170, Trp-243, and Phe-244. In this <scene name='90/904328/Zizwithaa/6'>cavity</scene>, N-dimethyl group on the ligand makes ion pairs with Asp-184 and Glu-164. The ligand is then stabilized by stacking its ring with Trp-248 and the Cys-168 to Cys-180 disulfide bond <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>.
 ===== Peptide =====
@@ Line 77: / Line 77: @@
 [[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/6'>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.
 This receptor is shallow and is able to bind to a variety of drugs, creating a need for a solution to mediate the effects of MRGPRX2 activation. Currently, there is research for the development of small antagonists that will induce an anti-inflammatory effect by preventing [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE-dependent] mast cell degranulation <ref name="McNeil">McNeil, B. D., et al. "MRGPRX2 and Adverse Drug Reactions." Frontier Immunology, 06 August 2021, https://www.frontiersin.org/articles/10.3389/fimmu.2021.676354/full</ref>. There are two antagonists that have been adapted from being antagonists to another Class A GPCR, [https://en.wikipedia.org/wiki/NK1_receptor_antagonist neurokinin-1 receptor (NK-1R)] <ref name="Ogasawara">Ogasawara, H., et al. "Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells." Journal of Leukocyte Biology, 12 July 2019, https://jlb.onlinelibrary.wiley.com/doi/10.1002/JLB.2AB1018-405R</ref>. Through the development of this research, these adverse side effects can be relieved and improve patient satisfaction.