Sandbox Reserved 1722: Difference between revisions

Line 1:

{{Template:CH462_Biochemistry_II_2022}}

== '''''Human Itch GPCR''''' ==

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

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

== G-Protein Coupled Receptors ==

Line 26:

Line 27:

===== ''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='90/904327/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. In MRGPRX2, the <scene name='90/904328/~~7tm_domain_pt_5~~/1'>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='90/904327/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. In MRGPRX2, the <scene name='90/904328/7tm_domain_pt_6/1'>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.

===== ''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 GPCR, like β2AR, the <scene name='90/904328/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_2~~/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='90/904328/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'' =====

Line 44:

Line 45:

===== Cation =====

[[Image: Zinc.PNG|250px|right|thumb|'''Figure 2''': Structure of R-Zinc 3573. A cationic ligand selected for binding to MRGPRX2. This ligand was used as a probe 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>]] <scene name='90/904327/Zinc/1'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2. 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='90/904327/Zizwithaa/2'>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>.

[[Image: Zinc.PNG|250px|right|thumb|'''Figure 2''': Structure of R-Zinc 3573. A cationic ligand selected for binding to MRGPRX2. This ligand was used as a probe 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>]]<scene name='90/904327/Zinc/1'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2. 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='90/904327/Zizwithaa/2'>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 =====

<scene name='90/904328/~~Overview_x2_c_pt_2~~/1'>Cortistatin-14</scene> is one of the peptide ligands that binds to MRGPRX2. Cortistatin-14 interacts with the binding pocket through an <scene name='90/904328/~~Zic14_pt_2~~/1'>electrostatic</scene> interaction in sub-pocket 1 between Lys-3 on the peptide and Glu-164 and Asp-184 on MRGPRX2 <ref name="Cao"/>. Additionally, there are hydrophobic interactions in sub-pocket 2 between the peptide and the binding pocket due to the large hydrophobic amino acids on Cortistatin-14. [[Image: Peptide.PNG|250px|left|thumb|'''Figure 3''': Structure of Cortistatin-14 with resolved amino acids highlighted in green.<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/Overview_x2_c_pt_3/1'>Cortistatin-14</scene>is one of the peptide ligands that binds to MRGPRX2. Cortistatin-14 interacts with the binding pocket through an <scene name='90/904328/Zic14_pt_3/2'>electrostatic</scene> interaction in sub-pocket 1 between Lys-3 on the peptide and Glu-164 and Asp-184 on MRGPRX2 <ref name="Cao"/>. Additionally, there are hydrophobic interactions in sub-pocket 2 between the peptide and the binding pocket due to the large hydrophobic amino acids on Cortistatin-14. [[Image: Peptide.PNG|250px|left|thumb|'''Figure 3''': Structure of Cortistatin-14 with resolved amino acids highlighted in green.<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>]]

Line 60:

Line 61:

== Clinical Relevance ==

[[Image: ~~Drugs~~.PNG|400px|right|thumb|'''Figure 4''': Structures of Dextromethorphan, Morphine, and Codeine.<ref name="Cao"/>]]

[[Image:Drugs_and_zinc.PNG|400px|right|thumb|'''Figure 4''': Structures of (R)-Zinc-3573, Dextromethorphan, Morphine, and Codeine. The red circles indicate conserved basic N-dimethyl group and the blue squares show the conserved benzene rings.<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>.

Sandbox Reserved 1722: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 1: / Line 1: @@
 {{Template:CH462_Biochemistry_II_2022}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
 == '''''Human Itch GPCR''''' ==
 <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:MP.PNG|350px|thumb|'''Figure 1''':MRGPRX2 in the cellular membrane. <ref name="Cao"/>]]
+[[Image:MP.PNG|350px|right|thumb|'''Figure 1''':MRGPRX2 in the cellular membrane. <ref name="Cao"/>]]
 == G-Protein Coupled Receptors ==
@@ Line 26: / Line 27: @@
 ===== ''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='90/904327/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. In MRGPRX2, the <scene name='90/904328/7tm_domain_pt_5/1'>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='90/904327/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. In MRGPRX2, the <scene name='90/904328/7tm_domain_pt_6/1'>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.
 ===== ''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 GPCR, like β2AR, the <scene name='90/904328/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_2/1'>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='90/904328/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'' =====
@@ Line 44: / Line 45: @@
 ===== Cation =====
-[[Image: Zinc.PNG|250px|right|thumb|'''Figure 2''': Structure of R-Zinc 3573. A cationic ligand selected for binding to MRGPRX2. This ligand was used as a probe 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>]] <scene name='90/904327/Zinc/1'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2. 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='90/904327/Zizwithaa/2'>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>.
+[[Image: Zinc.PNG|250px|right|thumb|'''Figure 2''': Structure of R-Zinc 3573. A cationic ligand selected for binding to MRGPRX2. This ligand was used as a probe 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>]]<scene name='90/904327/Zinc/1'>(R)-Zinc-3573</scene> is a cation ligand that selectively binds to MRGPRX2. 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='90/904327/Zizwithaa/2'>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 =====
-<scene name='90/904328/Overview_x2_c_pt_2/1'>Cortistatin-14</scene> is one of the peptide ligands that binds to MRGPRX2. Cortistatin-14 interacts with the binding pocket through an <scene name='90/904328/Zic14_pt_2/1'>electrostatic</scene> interaction in sub-pocket 1 between Lys-3 on the peptide and Glu-164 and Asp-184 on MRGPRX2 <ref name="Cao"/>. Additionally, there are hydrophobic interactions in sub-pocket 2 between the peptide and the binding pocket due to the large hydrophobic amino acids on Cortistatin-14. [[Image: Peptide.PNG|250px|left|thumb|'''Figure 3''': Structure of Cortistatin-14 with resolved amino acids highlighted in green.<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/Overview_x2_c_pt_3/1'>Cortistatin-14</scene>is one of the peptide ligands that binds to MRGPRX2. Cortistatin-14 interacts with the binding pocket through an <scene name='90/904328/Zic14_pt_3/2'>electrostatic</scene> interaction in sub-pocket 1 between Lys-3 on the peptide and Glu-164 and Asp-184 on MRGPRX2 <ref name="Cao"/>. Additionally, there are hydrophobic interactions in sub-pocket 2 between the peptide and the binding pocket due to the large hydrophobic amino acids on Cortistatin-14. [[Image: Peptide.PNG|250px|left|thumb|'''Figure 3''': Structure of Cortistatin-14 with resolved amino acids highlighted in green.<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>]]
@@ Line 60: / Line 61: @@
 == Clinical Relevance ==
-[[Image: Drugs.PNG|400px|right|thumb|'''Figure 4''': Structures of Dextromethorphan, Morphine, and Codeine.<ref name="Cao"/>]]
+[[Image:Drugs_and_zinc.PNG|400px|right|thumb|'''Figure 4''': Structures of (R)-Zinc-3573, Dextromethorphan, Morphine, and Codeine. The red circles indicate conserved basic N-dimethyl group and the blue squares show the conserved benzene rings.<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>.