Sandbox Reserved 1700: Difference between revisions

Line 7:

== Background ==

[https://en.wikipedia.org/wiki/G_protein-coupled_receptor GCPR]’s or G-Protein Coupled Receptors are a large family of protein receptors that promote cellular signaling and signal transduction <ref name= “Tuteja”>PMID: 19826234</ref>. GPCRs transmit extracellular signals to intracellular messages. Many essential pathways utilize GPCRs, including human vision by the GPCR [https://proteopedia.org/wiki/index.php/Rhodopsin Rhodopsin], and the adrenaline fight-or-flight response by the [https://proteopedia.org/wiki/index.php/Beta2_adrenergic_receptor-Gs_protein_complex_updated β2-adrenoceptor GPCR]. Understanding GPCR’s and how they produce their desired intracellular signal is essential to studying essential cellular pathways, especially in their diseased states. GCPRs are common drug targets, with 475 drugs acting on over 100 GPCRs. An additional 300 drugs are in clinical trial stages, and 20% of those drugs are targeting novel GPCRs <ref name="Hauser">PMID:29075003</ref>. Because of the clinical relevance of GPCRs, new structures provide new avenues for drug development to both treat disease or modulate the harmful side effects.

[https://en.wikipedia.org/wiki/G_protein-coupled_receptor GCPR]’s or G-Protein Coupled Receptors are a large family of protein receptors that promote cellular signaling and [https://en.wikipedia.org/wiki/Signal_transduction signal transduction]<ref name= “Tuteja”>PMID: 19826234</ref>. GPCRs transmit extracellular signals to intracellular messages. Many essential pathways utilize GPCRs, including human vision by the GPCR [https://proteopedia.org/wiki/index.php/Rhodopsin Rhodopsin], and the adrenaline fight-or-flight response by the [https://proteopedia.org/wiki/index.php/Beta2_adrenergic_receptor-Gs_protein_complex_updated β2-adrenoceptor GPCR]. Understanding GPCR’s and how they produce their desired intracellular signal is essential to studying essential cellular pathways, especially in their diseased states. GCPRs are common drug targets, with 475 drugs acting on over 100 GPCRs. An additional 300 drugs are in clinical trial stages, and 20% of those drugs are targeting novel GPCRs <ref name="Hauser">PMID:29075003</ref>. Because of the clinical relevance of GPCRs, new structures provide new avenues for drug development to both treat disease or modulate the harmful side effects.

Some cells in the human body that express the MRGPRX2 receptor include [https://en.wikipedia.org/wiki/Mast_cell mast cells] in the skin, intestines, and trachea <ref name="Porebski">PMID:30619367</ref><ref name="Dondalska">PMID: 33101278</ref>. Mast cells are immune cells responsible for triggering inflammatory responses ~~and~~ are densely packed with [https://en.wikipedia.org/wiki/Granule_(cell_biology) granules] containing inflammatory chemicals, such as [https://en.wikipedia.org/wiki/Histamine histamine]~~<ref name= "Dondalska" />~~ and [https://en.wikipedia.org/wiki/Heparin heparin]. Mast cells can be activated by either [https://en.wikipedia.org/wiki/Antibody antibodies] from the immune response or upon ligands binding to MRGPRX2 receptors on their surface<ref name="McNeil">PMID: 25517090</ref>. Upon activation, mast cells will release histamine-containing granules which can trigger a larger inflammatory response <ref name= "Dondalska" /><ref name="McNeil" />. These responses induce common allergic reaction or [https://en.wikipedia.org/wiki/~~Anaphylaxisanaphylaxis~~] symptoms, such as cutaneous itching sensations or airway constriction<ref name= "Cao" /><ref name= "Yang" /><ref name="McNeil">PMID: 25517090</ref>.

Some cells in the human body that express the MRGPRX2 receptor include [https://en.wikipedia.org/wiki/Mast_cell mast cells] in the skin, intestines, and trachea <ref name="Porebski">PMID:30619367</ref><ref name="Dondalska">PMID: 33101278</ref>. Mast cells are immune cells responsible for triggering [https://en.wikipedia.org/wiki/Inflammation inflammatory] responses. Mast cells are densely packed with [https://en.wikipedia.org/wiki/Granule_(cell_biology) granules] containing inflammatory chemicals, such as [https://en.wikipedia.org/wiki/Histamine histamine] and [https://en.wikipedia.org/wiki/Heparin heparin]<ref name= "Dondalska" />. Mast cells can be activated by either [https://en.wikipedia.org/wiki/Antibody antibodies] from the immune response or upon [https://en.wikipedia.org/wiki/Ligand ligands] binding to MRGPRX2 receptors on their surface<ref name="McNeil">PMID: 25517090</ref>. Upon activation, mast cells will release histamine-containing granules which can trigger a larger inflammatory response <ref name= "Dondalska" /><ref name="McNeil" />. These responses induce common allergic reaction or [https://en.wikipedia.org/wiki/Anaphylaxis anaphylaxis] symptoms, such as cutaneous itching sensations or airway constriction<ref name= "Cao" /><ref name= "Yang" /><ref name="McNeil">PMID: 25517090</ref>.

Ligands that bind to MRGPRX2 in the natural environment to produce an allergic response include [https://en.wikipedia.org/wiki/Exogeny#Biology_and_Medicine exogenous] molecules ~~such as~~ contents of insect venom, molecules like [https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75295 Compound 48/80 (C48/80)], or other polycationic molecules<ref name= "Dondalska">PMID: 33101278</ref><ref name= "Porebski" />. They can also respond to [https://en.wikipedia.org/wiki/Endogeny_(biology) endogenous] signaling molecules involved in inflammation pathways such as [https://en.wikipedia.org/wiki/Cytokine cytokines], [https://en.wikipedia.org/wiki/Anaphylatoxin anaphylatoxins], or [https://en.wikipedia.org/wiki/Neuropeptide#Receptor_targets neuropeptides]<ref name= "Porebski" />. Many pseudo-allergic drug reactions have been tied to overactivity of MRGPRX2 receptors on mast cells<ref name="McNeil">PMID: 25517090</ref>, so research into receptor-ligand interactions of the MRGPRX2 receptor has the potential to mediate many adverse itching and allergic reaction side effects seen in drugs today<ref name= "McNeil">PMID: 25517090</ref>.

Ligands that bind to MRGPRX2 in the natural environment to produce an allergic response include [https://en.wikipedia.org/wiki/Exogeny#Biology_and_Medicine exogenous] molecules, some being contents of insect venom, molecules like [https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75295 Compound 48/80 (C48/80)], or other polycationic molecules<ref name= "Dondalska">PMID: 33101278</ref><ref name= "Porebski" />. They can also respond to [https://en.wikipedia.org/wiki/Endogeny_(biology) endogenous] signaling molecules involved in inflammation pathways such as [https://en.wikipedia.org/wiki/Cytokine cytokines], [https://en.wikipedia.org/wiki/Anaphylatoxin anaphylatoxins], or [https://en.wikipedia.org/wiki/Neuropeptide#Receptor_targets neuropeptides]<ref name= "Porebski" />. Many pseudo-allergic drug reactions have been tied to overactivity of MRGPRX2 receptors on mast cells<ref name="McNeil">PMID: 25517090</ref>, so research into receptor-ligand interactions of the MRGPRX2 receptor has the potential to mediate many adverse itching and allergic reaction side effects seen in drugs today<ref name= "McNeil">PMID: 25517090</ref>.

GPCRs are categorized into 6 different classes based on shared sequences and functions. MRGPRX2 is categorized into the [https://proteopedia.org/wiki/index.php/GPCR#Family_A_of_GPCRs Class A] receptor family. However, itch receptors like MGPRX2 have unique structural features from most class A receptors <ref name="Cao">PMID: 34789874</ref><ref name="Yang">PMID: 34789875</ref>. These unique structural features, as seen in '''Class A Family Differences''', cause conformational changes throughout the protein that impact what ligands bind to the receptor<ref name= "Yang" />.

Line 24:

=== 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 <scene name='90/904306/Interface_2/1'>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.

[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_2/1'>interface</scene> ( '''Figure 2b'''). G-proteins are responsible for 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.]]

Sandbox Reserved 1700: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 7: / Line 7: @@
 == Background ==
-[https://en.wikipedia.org/wiki/G_protein-coupled_receptor GCPR]’s or G-Protein Coupled Receptors are a large family of protein receptors that promote cellular signaling and signal transduction <ref name= “Tuteja”>PMID: 19826234</ref>. GPCRs transmit extracellular signals to intracellular messages. Many essential pathways utilize GPCRs, including human vision by the GPCR [https://proteopedia.org/wiki/index.php/Rhodopsin Rhodopsin], and the adrenaline fight-or-flight response by the [https://proteopedia.org/wiki/index.php/Beta2_adrenergic_receptor-Gs_protein_complex_updated β2-adrenoceptor GPCR]. Understanding GPCR’s and how they produce their desired intracellular signal is essential to studying essential cellular pathways, especially in their diseased states. GCPRs are common drug targets, with 475 drugs acting on over 100 GPCRs. An additional 300 drugs are in clinical trial stages, and 20% of those drugs are targeting novel GPCRs <ref name="Hauser">PMID:29075003</ref>. Because of the clinical relevance of GPCRs, new structures provide new avenues for drug development to both treat disease or modulate the harmful side effects.
+[https://en.wikipedia.org/wiki/G_protein-coupled_receptor GCPR]’s or G-Protein Coupled Receptors are a large family of protein receptors that promote cellular signaling and [https://en.wikipedia.org/wiki/Signal_transduction signal transduction]<ref name= “Tuteja”>PMID: 19826234</ref>. GPCRs transmit extracellular signals to intracellular messages. Many essential pathways utilize GPCRs, including human vision by the GPCR [https://proteopedia.org/wiki/index.php/Rhodopsin Rhodopsin], and the adrenaline fight-or-flight response by the [https://proteopedia.org/wiki/index.php/Beta2_adrenergic_receptor-Gs_protein_complex_updated β2-adrenoceptor GPCR]. Understanding GPCR’s and how they produce their desired intracellular signal is essential to studying essential cellular pathways, especially in their diseased states. GCPRs are common drug targets, with 475 drugs acting on over 100 GPCRs. An additional 300 drugs are in clinical trial stages, and 20% of those drugs are targeting novel GPCRs <ref name="Hauser">PMID:29075003</ref>. Because of the clinical relevance of GPCRs, new structures provide new avenues for drug development to both treat disease or modulate the harmful side effects.
-Some cells in the human body that express the MRGPRX2 receptor include [https://en.wikipedia.org/wiki/Mast_cell mast cells] in the skin, intestines, and trachea <ref name="Porebski">PMID:30619367</ref><ref name="Dondalska">PMID: 33101278</ref>. Mast cells are immune cells responsible for triggering inflammatory responses and are densely packed with [https://en.wikipedia.org/wiki/Granule_(cell_biology) granules] containing inflammatory chemicals, such as [https://en.wikipedia.org/wiki/Histamine histamine]<ref name= "Dondalska" /> and [https://en.wikipedia.org/wiki/Heparin heparin]. Mast cells can be activated by either [https://en.wikipedia.org/wiki/Antibody antibodies] from the immune response or upon ligands binding to MRGPRX2 receptors on their surface<ref name="McNeil">PMID: 25517090</ref>. Upon activation, mast cells will release histamine-containing granules which can trigger a larger inflammatory response <ref name= "Dondalska" /><ref name="McNeil" />. These responses induce common allergic reaction or [https://en.wikipedia.org/wiki/Anaphylaxisanaphylaxis] symptoms, such as cutaneous itching sensations or airway constriction<ref name= "Cao" /><ref name= "Yang" /><ref name="McNeil">PMID: 25517090</ref>.
+Some cells in the human body that express the MRGPRX2 receptor include [https://en.wikipedia.org/wiki/Mast_cell mast cells] in the skin, intestines, and trachea <ref name="Porebski">PMID:30619367</ref><ref name="Dondalska">PMID: 33101278</ref>. Mast cells are immune cells responsible for triggering [https://en.wikipedia.org/wiki/Inflammation inflammatory] responses. Mast cells are densely packed with [https://en.wikipedia.org/wiki/Granule_(cell_biology) granules] containing inflammatory chemicals, such as [https://en.wikipedia.org/wiki/Histamine histamine] and [https://en.wikipedia.org/wiki/Heparin heparin]<ref name= "Dondalska" />. Mast cells can be activated by either [https://en.wikipedia.org/wiki/Antibody antibodies] from the immune response or upon [https://en.wikipedia.org/wiki/Ligand ligands] binding to MRGPRX2 receptors on their surface<ref name="McNeil">PMID: 25517090</ref>. Upon activation, mast cells will release histamine-containing granules which can trigger a larger inflammatory response <ref name= "Dondalska" /><ref name="McNeil" />. These responses induce common allergic reaction or [https://en.wikipedia.org/wiki/Anaphylaxis anaphylaxis] symptoms, such as cutaneous itching sensations or airway constriction<ref name= "Cao" /><ref name= "Yang" /><ref name="McNeil">PMID: 25517090</ref>.
-Ligands that bind to MRGPRX2 in the natural environment to produce an allergic response include [https://en.wikipedia.org/wiki/Exogeny#Biology_and_Medicine exogenous] molecules such as contents of insect venom, molecules like [https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75295 Compound 48/80 (C48/80)], or other polycationic molecules<ref name= "Dondalska">PMID: 33101278</ref><ref name= "Porebski" />. They can also respond to [https://en.wikipedia.org/wiki/Endogeny_(biology) endogenous] signaling molecules involved in inflammation pathways such as [https://en.wikipedia.org/wiki/Cytokine cytokines], [https://en.wikipedia.org/wiki/Anaphylatoxin anaphylatoxins], or [https://en.wikipedia.org/wiki/Neuropeptide#Receptor_targets neuropeptides]<ref name= "Porebski" />. Many pseudo-allergic drug reactions have been tied to overactivity of MRGPRX2 receptors on mast cells<ref name="McNeil">PMID: 25517090</ref>, so research into receptor-ligand interactions of the MRGPRX2 receptor has the potential to mediate many adverse itching and allergic reaction side effects seen in drugs today<ref name= "McNeil">PMID: 25517090</ref>.
+Ligands that bind to MRGPRX2 in the natural environment to produce an allergic response include [https://en.wikipedia.org/wiki/Exogeny#Biology_and_Medicine exogenous] molecules, some being contents of insect venom, molecules like [https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75295 Compound 48/80 (C48/80)], or other polycationic molecules<ref name= "Dondalska">PMID: 33101278</ref><ref name= "Porebski" />. They can also respond to [https://en.wikipedia.org/wiki/Endogeny_(biology) endogenous] signaling molecules involved in inflammation pathways such as [https://en.wikipedia.org/wiki/Cytokine cytokines], [https://en.wikipedia.org/wiki/Anaphylatoxin anaphylatoxins], or [https://en.wikipedia.org/wiki/Neuropeptide#Receptor_targets neuropeptides]<ref name= "Porebski" />. Many pseudo-allergic drug reactions have been tied to overactivity of MRGPRX2 receptors on mast cells<ref name="McNeil">PMID: 25517090</ref>, so research into receptor-ligand interactions of the MRGPRX2 receptor has the potential to mediate many adverse itching and allergic reaction side effects seen in drugs today<ref name= "McNeil">PMID: 25517090</ref>.
 GPCRs are categorized into 6 different classes based on shared sequences and functions. MRGPRX2 is categorized into the [https://proteopedia.org/wiki/index.php/GPCR#Family_A_of_GPCRs Class A] receptor family. However, itch receptors like MGPRX2 have unique structural features from most class A receptors <ref name="Cao">PMID: 34789874</ref><ref name="Yang">PMID: 34789875</ref>. These unique structural features, as seen in '''Class A Family Differences''', cause conformational changes throughout the protein that impact what ligands bind to the receptor<ref name= "Yang" />.
@@ Line 24: / Line 24: @@
 === 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  <scene name='90/904306/Interface_2/1'>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.
+[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_2/1'>interface</scene> ( '''Figure 2b'''). G-proteins are responsible for 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.]]