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side='right' caption='MRGPRX2 is a specific type of GPCR. Its transmembrane domain (red) spans the phospholipid bilayer of cellular membranes and attaches to the G-protein. The G-protein consists of 3 different domains: alpha (blue), beta (magenta), and gamma (yellow). scene ='90/904305/Structure_overview/2'>

[[Image:MRGPRX2_within_membrane.png|500px|right|thumb|'''Figure 1.''' MRGPRX2 as it sits within the cellular membrane. Phospholipid bilayer is represented by grey dots, with labeled cellular locations]]

GCPR’s or G-Protein Coupled Receptors are a special type of protein receptor that promotes cellular signaling. Due to its structure spanning the cellular membrane, it works to transmit extracellular signals to create a change inside the cell. This is called signal transduction, and is a common way extracellular signals produce a change within cells. Some common cellular pathways that utilize GPCR’s are found in [https://proteopedia.org/wiki/index.php/Rhodopsin Rhodopsin], a protein essential for the human vision response, or the [https://proteopedia.org/wiki/index.php/Beta2_adrenergic_receptor-Gs_protein_complex_updated adrenaline fight-or-flight response]. Understanding GPCR’s and how they produce their desired intracellular signal is essential understanding essential cellular pathways, especially in their diseased states. As of 2017, there were about 475 drugs in circulation that acted on 108 GPCR targets, and at least 321 GPCR-targeting drugs were in clinical trial stages, with about 20% of them targeting novel GPCR’s. <ref name="Hauser">PMID:29075003</ref> Because of the clinical relevance of GPCR’s, every new structure found, such as MRGPRX2, contributes to essential drug development to both treat disease, or modulate harmful side effects.  

Because of how many different types of GPCR’s there are, they have been categorized into 6 different classes based on shared sequences and functions.<ref name="Basith">PMID:29593527</ref> MRGPRX2 is categorized into the [https://proteopedia.org/wiki/index.php/GPCR#Family_A_of_GPCRs Class A] receptor family, however it has important differences that make it a unique type of Class A receptor. <ref name="Cao">PMID: 34789874</ref><ref name="Yang">PMID: 34789875</ref>

Cryo-electron microscopy (cryo-EM) was used to image the MRGPRX2 receptor to analyze its structure. <ref name= "Cao" /> <ref name= "Yang" /> which helped to classify it into the A family of GPCR's. MRGPRX2 therefore shares the same general structural domains of all GPCR's. This includes a <scene name='90/904305/Structure_overview_red/1'>transmembrane domain</scene> and a <scene name='90/904305/Structure_overview_gprotein/1'>G-protein</scene> domain. The G-protein domain consists of <scene name='90/904305/Structure_overview_alpha/1'>alpha</scene>, <scene name='90/904305/Structure_overview_beta/1'>beta</scene>, and <scene name='90/904305/Structure_overview_gamma/1'>gamma</scene> subunits. In preparing the protein sample, MRGPRX2 was prepared with the <scene name='90/904305/Antibody_representation/1'>antibody scFv16</scene> in order to stabilize the membrane for proper imaging. For simplicity and to focus on the specific MRGPRX2 receptor, the antibody has been removed.  

The transmembrane domain spans the cellular membrane. It consists of <scene name='90/904305/Transmembrane_protein_c_and_l/1'>seven transmembrane helices</scene> and <scene name='90/904305/Ecl_and_icl/2'>6 loops</scene> (three extracellular loops, and three intracellular loops). The transmembrane helices are numbered 1-7 and contain special conserved motifs that are shared across other A family receptors. These motifs are expanded upon later, as they heavily contribute to the structure and therefore function of the transmembrane domain as a whole.

The extracellular domain of the protein is responsible for ligand binding, which initiates signal transduction. The properties of the extracellular environment of the transmembrane domain determines what ligands bind to the protein, and what type of binding interactions the protein and ligand have. In MRGPRX2, the extracellular side of the protein has one binding pocket with <scene name='90/904305/Subpockets_1_and_2/2'>two sub-pockets</scene>. Sub-pocket 1 is negatively charged due to negatively charged <scene name='90/904305/Subpockets_1_and_2_d_and_e/1'>Aspartate and Glutamate</scene> residues (D184 and E164), while sub-pocket 2 contains hydrophobic amino acids which contribute to hydrophobic interactions between the ligand and protein.  

The intracellular domain is what connects the transmembrane and G-protein domains together. There are a wide variety of residues and important interactions that contribute to this interaction, and it is very important in transmitting the extracellular signal of ligand binding to the intracellular environment where the G-protein binds and can become activated.  

[https://proteopedia.org/wiki/index.php/G_protein GTP-binding proteins], also known as G-proteins, are heterotrimeric complexes consisting of alpha, beta, and gamma subunits that interact with membrane receptor proteins. G-proteins are responsible transmitting extracellular signals into the cell upon activation. This activation happens when the alpha subunit of the G-protein binds GTP instead of GDP, and then disassociates from the rest of the protein, initiating the intracellular signaling cascade. There are different families of G-alpha subunits, Gαi, Gαs, Gα12/13, and Gαq <ref name="Kamato">PMID: 26664886</ref>. MRGPRX2 has been found to bind both Gαi and Gαq subunits with relatively no major structural changes between the two despite slightly different amino acids present <ref name= "Cao" /> <ref name= "Yang" />. Throughout this page, MGPRX2 is always shown with Gq. '''Figure 2a''' shows the overlay of MGPRX2 with either the Gq or Gi alpha subunit. '''Figure 2b''' shows the specific residues involved in the <scene name='90/904306/Interface_2/1'>interface</scene> between the membrane receptor and G protein. The major difference between the two comes from one amino acid difference (valine on Gq versus phenylalanine on Gi) that pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein. This is the only major structural difference between Gq and Gi subunits.  

[[Image:Gq and gi overlay.png|500px|center|thumb|'''Figure 2a.''' Overlay of MGPRX2-Gq (red-dark blue) and MGPRX2-Gi (cyan-yellow). '''Figure 2b.''' Important residues involved in the interface between MGPRX2 and Gq/ Gi subunits. Arrow pointing to the major difference between the interfaces, which comes from the final C-terminus residue on the G-alpha subunit. In Gq, there is a valine while in Gi, there is a phenylalanine. This pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein.]]