Sandbox Reserved 1701: Difference between revisions
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=== G-Protein === | === G-Protein === | ||
[https://proteopedia.org/wiki/index.php/G_protein GTP-binding proteins], also known as G-proteins, are heterotrimeric complexes consisting of <scene name=''90/904305/Structure_overview_alpha/2'>alpha</scene>, <scene name='90/904305/Structure_overview_beta/2'>beta</scene>, and <scene name='90/904305/Structure_overview_gamma/2'>gamma</scene> subunits that interact with the intracellular transmembrane region at an | [https://proteopedia.org/wiki/index.php/G_protein GTP-binding proteins], also known as G-proteins, are heterotrimeric complexes consisting of <scene name=''90/904305/Structure_overview_alpha/2'>alpha</scene>, <scene name='90/904305/Structure_overview_beta/2'>beta</scene>, and <scene name='90/904305/Structure_overview_gamma/2'>gamma</scene> subunits that interact with the intracellular transmembrane region at an <scene name='90/904306/Interface_2/2'>interface</scene> ( '''Figure 2b'''). G-proteins are responsible for [https://en.wikipedia.org/wiki/Signal_transduction transmitting] extracellular signals into the cell upon activation. Activation leads to a substitution of GDP with GTP within the alpha subunit, causing the alpha subunit to disassociate from the beta and gamma subunits to initiate an intracellular signaling cascade. There are different families of G-alpha subunits, Gαi, Gαs, Gα12/13, and Gαq <ref name="Kamato">PMID: 26664886</ref>. MRGPRX2 binds to both Gαi and Gαq subunits with nearly identical structures despite slightly different amino acids present ( '''Figure 2a''') <ref name= "Cao" /> <ref name= "Yang" />. Throughout this page, MGPRX2 is always shown with Gq. The major difference between the Gq and Gi bound structures 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. | ||
[[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. All other interactions are nearly identical. PDBs: (MRGPRX2-Gq):7s8l and (MRGPRX2-Gi):7s8m]] | [[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. All other interactions are nearly identical. PDBs: (MRGPRX2-Gq):7s8l and (MRGPRX2-Gi):7s8m]] | ||
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[[Image:Screen Shot 2022-03-15 at 10.23.20 AM.png|200px|left|thumb|'''Figure 4.''' ERC Motif of MRGPRX2 with key residues shown as ball and stick. PDB: 7s8l.]] | [[Image:Screen Shot 2022-03-15 at 10.23.20 AM.png|200px|left|thumb|'''Figure 4.''' ERC Motif of MRGPRX2 with key residues shown as ball and stick. PDB: 7s8l.]] | ||
The E/DRY motif in most class A GPCRs is responsible for forming salt bridges with surrounding residues and TM6<ref name="Rovati">PMID: 17192495</ref>. These salt bridges maintain the inactive conformation of the receptor until ligand binding breaks the ionic "lock" from these interactions. MRGPRX2 has an ERC motif <scene name='90/904306/Alignment_erc/2'>rather than</scene> the typically [https://proteopedia.org/wiki/index.php/A_Physical_Model_of_the_%CE%B22-Adrenergic_Receptor#conserved%20DRY%20motif conserved E/DRY Motif] in other class A GPCRs such as 5HT2AR and the adrenergic receptor. The amino acid residue shift from TYR-174 to CYS-128 allows compaction of the helices in MRGPRX2 where the standard TYR physically pushes the TMD helices apart('''Figure 4'''). The conserved residues E and R still form salt bridges with nearby residues. This and the closer packing of the helices contribute to a less significant TMD conformational change upon ligand binding ('''Figure 10'''). | The E/DRY motif in most class A GPCRs is responsible for forming salt bridges with surrounding residues and TM6<ref name="Rovati">PMID: 17192495</ref>. These salt bridges maintain the inactive conformation of the receptor until ligand binding breaks the ionic "lock" from these interactions. MRGPRX2 has an ERC motif <scene name='90/904306/Alignment_erc/2'>rather than</scene> the typically [https://proteopedia.org/wiki/index.php/A_Physical_Model_of_the_%CE%B22-Adrenergic_Receptor#conserved%20DRY%20motif conserved E/DRY Motif] in other class A GPCRs such as 5HT2AR and the adrenergic receptor. The amino acid residue shift from TYR-174 to CYS-128 allows compaction of the helices in MRGPRX2 where the standard TYR physically pushes the TMD helices apart('''Figure 4'''). The conserved residues E and R still form salt bridges with nearby residues. This and the closer packing of the helices contribute to a less significant TMD conformational change upon ligand binding ('''Figure 10'''). | ||
