Sandbox Reserved 1700: Difference between revisions

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=== Transmembrane Domain ===

The [https://en.wikipedia.org/wiki/Transmembrane_domain#:~:text=A%20transmembrane%20domain%20(TMD)%20is,can%20adopt%20a%20different%20conformation. transmembrane domain] spans the cell membrane ('''Figure 1''') and it consists of <scene name='90/904305/Transmembrane_protein_c_and_l/2'>seven transmembrane α-helices</scene> and <scene name='90/904305/Ecl_and_icl/3'>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 region of the 7 transmembrane domain forms a single [https://en.wikipedia.org/wiki/Binding_site binding pocket] with <scene name='90/904305/Subpockets_1_and_2/4'>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/2'>aspartate and glutamate</scene> residues (Asp-184 and Glu-164), while sub-pocket 2 contains hydrophobic amino acids which contribute to hydrophobic interactions between the ligand and protein.

The extracellular region of the 7 transmembrane domain forms a single [https://en.wikipedia.org/wiki/Binding_site binding pocket] with <scene name='90/904305/Subpockets_1_and_2/4'>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/2'>aspartate and glutamate</scene> residues (Asp-184 and Glu-164), while sub-pocket 2 contains hydrophobic amino acids which contribute to hydrophobic interactions between the ligand and protein. The intracellular region ('''Figure 1''') is what connects the transmembrane helices with the G-protein.

The intracellular region ('''Figure 1''') is what connects the transmembrane helices with the G-protein.

This GPCR has been modeled both as MRGPRX2 and MRGPRX4<ref name="Cao">PMID: 34789874</ref><ref name="Yang">PMID: 34789875</ref>, though much of this page focusses on MRGPRX2. X4 is found to mediate cholestatic itch compared to X2's regulation of mast cell degranulation and hypersensitivity itch-reactions<ref name="Cao">PMID: 34789874</ref>. X4 and X2 demonstrate nearly the same structural differences compared to that of other class A GPCRs. Interestingly, X4 can interact with negatively charged bile acids and is insensitive to the common X2 cationic agonists discussed later ('''Figure 7''').

=== G-Protein ===

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== Function ==

[[Image:Screen Shot 2022-04-162 at 2.49.26 PM.png|420px|right|thumb|'''Figure 8.'''Schematic representation of cellular response]]

GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] (~~figure~~ 8)<ref name="Porebski">PMID: 30619367</ref>.

GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] ('''Figure 8''')<ref name="Porebski">PMID: 30619367</ref>.

=== Before Activation ===

The culmination of different motifs observed in MRGPRX2 compared to other class A GPCRs leads to external membrane ligand binding. The MRGPRX2 GPCR undergoes a much smaller conformational change upon ligand binding compared to other Class A GPCRs due to surface level binding versus deep helix binding ('''Figure 9'''). This smaller change can be seen as only minor extracellular movement occurs in MRGRPX2 upon binding compared to other GPCRs which can undergo loop and helical conformational changes<ref name="Hoffmann">PMID: 18059316</ref>.

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=== After Activation ===

After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files 1bof and 1cip.

After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files [https://www.rcsb.org/structure/1BOF 1bof] and [https://www.rcsb.org/structure/1CIP 1cip].

[[Image:Screen Shot 2022-03-282 at 6.59.44 PM.png|500px|center|thumb|'''Figure 9.''' Overlay of unbound (transparent) and bound (opaque) transmembrane proteins of both MRGRPX2 (left) and 5-HT2AR (right). PDBs: (MRGPRX2): 7s8l and (5HT2A): 6wha.]]

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@@ Line 20: / Line 20: @@
 === Transmembrane Domain ===
 The [https://en.wikipedia.org/wiki/Transmembrane_domain#:~:text=A%20transmembrane%20domain%20(TMD)%20is,can%20adopt%20a%20different%20conformation. transmembrane domain] spans the cell membrane ('''Figure 1''') and it consists of <scene name='90/904305/Transmembrane_protein_c_and_l/2'>seven transmembrane α-helices</scene> and <scene name='90/904305/Ecl_and_icl/3'>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 region of the 7 transmembrane domain forms a single [https://en.wikipedia.org/wiki/Binding_site binding pocket] with <scene name='90/904305/Subpockets_1_and_2/4'>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/2'>aspartate and glutamate</scene> residues (Asp-184 and Glu-164), while sub-pocket 2 contains hydrophobic amino acids which contribute to hydrophobic interactions between the ligand and protein.
+The extracellular region of the 7 transmembrane domain forms a single [https://en.wikipedia.org/wiki/Binding_site binding pocket] with <scene name='90/904305/Subpockets_1_and_2/4'>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/2'>aspartate and glutamate</scene> residues (Asp-184 and Glu-164), while sub-pocket 2 contains hydrophobic amino acids which contribute to hydrophobic interactions between the ligand and protein. The intracellular region ('''Figure 1''') is what connects the transmembrane helices with the G-protein.
-The intracellular region ('''Figure 1''') is what connects the transmembrane helices with the G-protein.
+This GPCR has been modeled both as MRGPRX2 and MRGPRX4<ref name="Cao">PMID: 34789874</ref><ref name="Yang">PMID: 34789875</ref>, though much of this page focusses on MRGPRX2. X4 is found to mediate cholestatic itch compared to X2's regulation of mast cell degranulation and hypersensitivity itch-reactions<ref name="Cao">PMID: 34789874</ref>. X4 and X2 demonstrate nearly the same structural differences compared to that of other class A GPCRs. Interestingly, X4 can interact with negatively charged bile acids and is insensitive to the common X2 cationic agonists discussed later ('''Figure 7''').
 === G-Protein ===
@@ Line 97: / Line 98: @@
 == Function ==
 [[Image:Screen Shot 2022-04-162 at 2.49.26 PM.png|420px|right|thumb|'''Figure 8.'''Schematic representation of cellular response]]
-GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] (figure 8)<ref name="Porebski">PMID: 30619367</ref>.
+GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] ('''Figure 8''')<ref name="Porebski">PMID: 30619367</ref>.
 === Before Activation ===
 The culmination of different motifs observed in MRGPRX2 compared to other class A GPCRs leads to external membrane ligand binding. The MRGPRX2 GPCR undergoes a much smaller conformational change upon ligand binding compared to other Class A GPCRs due to surface level binding versus deep helix binding ('''Figure 9'''). This smaller change can be seen as only minor extracellular movement occurs in MRGRPX2 upon binding compared to other GPCRs which can undergo loop and helical conformational changes<ref name="Hoffmann">PMID: 18059316</ref>.
@@ Line 103: / Line 104: @@
 === After Activation ===
-After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files 1bof and 1cip.
+After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files [https://www.rcsb.org/structure/1BOF 1bof] and [https://www.rcsb.org/structure/1CIP 1cip].
 [[Image:Screen Shot 2022-03-282 at 6.59.44 PM.png|500px|center|thumb|'''Figure 9.''' Overlay of unbound (transparent) and bound (opaque) transmembrane proteins of both MRGRPX2 (left) and 5-HT2AR (right). PDBs: (MRGPRX2): 7s8l and (5HT2A): 6wha.]]