Sandbox Reserved 1722: Difference between revisions
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MRGPRX2 consists of two binding pockets (seen in Figure 3). Sub-pocket 1 consists of acidic catalytic residues Asp-184 and Glu-164 that interact with substrates by making ion pairs. There are also some hydrophobic aromatic residues, Phe-170, Trp-243, and Phe-244, towards the top of the binding pocket <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>. These residues provide stabilization with ligands through stacking. Lastly, this pocket is in close proximity with the commonly conserved disulfide bond (formed by Cys-168 and Cys-180) seen in most Class A GPCRs. The second binding pocket forms hydrophobic interactions with larger substrates (seen in Figure 2) but is generally less studied <ref name="Cao"/>. | MRGPRX2 consists of two binding pockets (seen in Figure 3). Sub-pocket 1 consists of acidic catalytic residues Asp-184 and Glu-164 that interact with substrates by making ion pairs. There are also some hydrophobic aromatic residues, Phe-170, Trp-243, and Phe-244, towards the top of the binding pocket <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>. These residues provide stabilization with ligands through stacking. Lastly, this pocket is in close proximity with the commonly conserved disulfide bond (formed by Cys-168 and Cys-180) seen in most Class A GPCRs. The second binding pocket forms hydrophobic interactions with larger substrates (seen in Figure 2) but is generally less studied <ref name="Cao"/>. | ||
[[Image:Electro.PNG|450px|center|thumb|'''Figure 3''': Binding pocket of MRGPRX2 with cortistatin-14. Two different binding pockets are present in MRGPRX2 and cortistatin-14 interacts with both of them | [[Image:Electro.PNG|450px|center|thumb|'''Figure 3''': Binding pocket of MRGPRX2 with cortistatin-14. Two different binding pockets are present in MRGPRX2 and cortistatin-14 interacts with both of them <ref name="Cao"/>.]] | ||
==== Agonists ==== | ==== Agonists ==== | ||
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=== 2. MRGPRX2 interaction with G-Protein === | === 2. MRGPRX2 interaction with G-Protein === | ||
[[Image:Gq_and_Gi_snip.PNG|300px|right|thumb|'''Figure 5''': Comparison of the conformational change for MRGPRX2 (light blue) coupled with Gq (teal) and MRGPRX2 (pink) coupled with Gi (purple) | [[Image:Gq_and_Gi_snip.PNG|300px|right|thumb|'''Figure 5''': Comparison of the conformational change for MRGPRX2 (light blue) coupled with Gq (teal) and MRGPRX2 (pink) coupled with Gi (purple) <ref name="Cao"/>. (PDB entry: [https://www.rcsb.org/structure/7S8N 7S8N] and [https://www.rcsb.org/structure/7S8O 7S8O])]] | ||
Once the ligand is bound, MRGPRX2 undergoes a conformational change that is transmitted through to the [https://en.wikipedia.org/wiki/G_protein#:~:text=G%20proteins%2C%20also%20known%20as,a%20cell%20to%20its%20interior. G-protein]. This conformational change is affected by the aforementioned deviances from Class A GPCRs. Rather than a large conformational change, a subtle one is induced. This will allow MRGPRX2 to interact with a G-protein. <scene name='90/904327/Gproteins/2'>G-proteins</scene> are composed of 3 subunits: α, β, and γ. When activated, the receptor acts as a [https://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factor Guanine nucleotide factor (GEF)]which will allow the Gα subunit to have its GDP be replaced by a GTP. This will cause the Gα subunit to dissociate from the dimer Gβγ <ref name="Ramesh">Ramesh, Soliman, et al. (2015) "G-Protein Coupled Receptors (GPCRs): A Comprehensive Computational Perspective." Combinational Chemistry and High Throughout Screening, 18(4), 346-364, https://pubmed.ncbi.nlm.nih.gov/25747435/</ref>. They are characterized by conserved motifs including DRY, PIF, Sodium Binding, and the CWxP <ref name="Zhou">PMID: 31855179</ref>. The Gα subunit is then able to act as a secondary messenger to begin the signal transduction in the cell. MRGPRX2 interacts with two different types of G-proteins; Gi and Gq. These G-proteins are activated by similar interactions with the receptor due to their similar structures (Figure 5). | Once the ligand is bound, MRGPRX2 undergoes a conformational change that is transmitted through to the [https://en.wikipedia.org/wiki/G_protein#:~:text=G%20proteins%2C%20also%20known%20as,a%20cell%20to%20its%20interior. G-protein]. This conformational change is affected by the aforementioned deviances from Class A GPCRs. Rather than a large conformational change, a subtle one is induced. This will allow MRGPRX2 to interact with a G-protein. <scene name='90/904327/Gproteins/2'>G-proteins</scene> are composed of 3 subunits: α, β, and γ. When activated, the receptor acts as a [https://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factor Guanine nucleotide factor (GEF)]which will allow the Gα subunit to have its GDP be replaced by a GTP. This will cause the Gα subunit to dissociate from the dimer Gβγ <ref name="Ramesh">Ramesh, Soliman, et al. (2015) "G-Protein Coupled Receptors (GPCRs): A Comprehensive Computational Perspective." Combinational Chemistry and High Throughout Screening, 18(4), 346-364, https://pubmed.ncbi.nlm.nih.gov/25747435/</ref>. They are characterized by conserved motifs including DRY, PIF, Sodium Binding, and the CWxP <ref name="Zhou">PMID: 31855179</ref>. The Gα subunit is then able to act as a secondary messenger to begin the signal transduction in the cell. MRGPRX2 interacts with two different types of G-proteins; Gi and Gq. These G-proteins are activated by similar interactions with the receptor due to their similar structures (Figure 5). | ||
