Sandbox Reserved 1723: Difference between revisions
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The sodium site motif facilitates the conformational change of GPCR upon activation.<ref name="Katritch">PMID: 24767681</ref> A sodium molecule sits in the middle of the TM7 helices where it is stabilized by conserved residues aspartate (TM2), serine (TM2), and three water molecules. The sodium is able to make a salt bridge with the aspartate at this position. The sodium acts similar to a ball joint in which it allows for the TM helices be spread apart and induce larger conformational change upon binding. In MRGPRX2 this motif is only partially conserved. The aspartate (TM2) is conserved while the serine is replaced by a glycine.<ref name="Yang"/> This creates a less favorable environment for the stabilization of sodium. Currently, in crystallization structures no sodium has been seen at this site. Thus making it inconclusive on whether it plays a role in the conformational change to activate G-proteins upon binding to the receptor.<ref name="Yang"/> | The sodium site motif facilitates the conformational change of GPCR upon activation.<ref name="Katritch">PMID: 24767681</ref> A sodium molecule sits in the middle of the TM7 helices where it is stabilized by conserved residues aspartate (TM2), serine (TM2), and three water molecules. The sodium is able to make a salt bridge with the aspartate at this position. The sodium acts similar to a ball joint in which it allows for the TM helices be spread apart and induce larger conformational change upon binding. In MRGPRX2 this motif is only partially conserved. The aspartate (TM2) is conserved while the serine is replaced by a glycine.<ref name="Yang"/> This creates a less favorable environment for the stabilization of sodium. Currently, in crystallization structures no sodium has been seen at this site. Thus making it inconclusive on whether it plays a role in the conformational change to activate G-proteins upon binding to the receptor.<ref name="Yang"/> | ||
== Binding Pocket == | |||
== MRGPRX2 Signaling Pathway == | |||
== 1. Binding Pocket == | |||
MRGPRX2 consists of two binding pockets (seen in Figure 2). Sub-pocket 1 consists of primarily hydrophobic aromatic residues; Phe-170, Trp-243, and Phe-244.<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. This pocket also contains acidic catalytic residues Asp-184 and Glu-164 that interact with substrates by making ion pairs. 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 electrostatic 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 2). Sub-pocket 1 consists of primarily hydrophobic aromatic residues; Phe-170, Trp-243, and Phe-244.<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. This pocket also contains acidic catalytic residues Asp-184 and Glu-164 that interact with substrates by making ion pairs. 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 electrostatic interactions with larger substrates (seen in Figure 2), but is generally less studied.<ref name="Cao"/> | ||
[[Image:Electro.PNG|450px|center|thumb|'''Figure 2''': 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"/>]] | [[Image:Electro.PNG|450px|center|thumb|'''Figure 2''': 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=== | |||
MRGPRX2 interacts with two different types of [https://en.wikipedia.org/wiki/G_protein#:~:text=G%20proteins%2C%20also%20known%20as,a%20cell%20to%20its%20interior. G-proteins], Gi and Gq. When activated these G-proteins will initiate the signal transduction pathway. These G-proteins are composed of 3 subunits; α, β, and γ. | |||
=== 3.After G-Protein Activation=== | === 3.After G-Protein Activation=== | ||
