Sandbox Reserved 1703: Difference between revisions

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===Inactive State===

A few hallmarks of the <scene name='90/904308/Inactive_structure/1'>inactive structure</scene> of mGlu2 are the <scene name='90/904307/Better_inactive_structure/3'>VFT</scene> in the open conformation, well separated <scene name='90/904307/Better_inactive_structure/2'>CRD</scene>, and distinct orientation of the 7TM. The most critical component of the inactive form is the ~~<scene name='90/904307/Tmd_helices/4'>~~asymmetric TM3-TM4 interface~~</scene>~~ formed by the 7 α-helices in the α and β chains of the 7TM. The inactive structure of mGlu2 is mediated mainly by helices 3 and 4 on both the α and β chains of the dimer through hydrophobic interactions. These <scene name='90/904307/Tm3-tm4_hydrophobic/2'>hydrophobic interactions</scene> between both transmembrane helices stabilize inactive conformation of mGlu2<ref name="Lin"/>.

A few hallmarks of the <scene name='90/904308/Inactive_structure/1'>inactive structure</scene> of mGlu2 are the <scene name='90/904307/Better_inactive_structure/3'>VFT</scene> in the open conformation, well separated <scene name='90/904307/Better_inactive_structure/2'>CRD</scene>, and distinct orientation of the 7TM. The most critical component of the inactive form is the asymmetric TM3-TM4 interface formed by the 7 α-helices in the α and β chains of the 7TM. The inactive structure of mGlu2 is mediated mainly by helices 3 and 4 on both the α and β chains of the dimer through hydrophobic interactions. These <scene name='90/904307/Tm3-tm4_hydrophobic/2'>hydrophobic interactions</scene> between both transmembrane helices stabilize inactive conformation of mGlu2<ref name="Lin"/>.

[[Image:Schematic of mGlu2.jpg|400 px|left|thumb|'''Figure 3.''' Demonstrates the conformational changes of mGlu2.]]

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===PAM and NAM Bound Form===

Moving from the intermediate state, a second glutamate will bind in the other lobe of the VFT. This will help close the VFT and move the CRD closer together <ref name="Seven" />. A positive allosteric modulator (PAM) or a negative allosteric modulator (NAM) will then come in and bind to mGlu2. PAM and NAM induce different conformational changes, which result in different outcomes. <scene name='90/904308/Pam/3'>PAM binds</scene> the TMD and promotes greater affinity for the binding of the G-protein. There are different types of PAMs that can bind to the TMD but this page focuses on JNJ-40411813<ref name="Lin"/>. PAM binds in a binding pocket that is created by helices 3, 5, 6, and 7 in the <scene name='90/904307/Tmd_helices/4'>TMD</scene>. Within helix 6, the hydrophobic binding is composed of W773, F776, L777, and F780. Due to spatial hindrance caused by the binding of PAM, helix 6 is shifted downward, causing reorientation of the TMD. This reorientation creates a cleft in the TMD for the G-protein to bind<ref name="Lin"/>. NAM, however, reduces the affinity for G protein binding. <scene name='90/904308/Nam_bound/2'>NAM binds</scene> to the same binding pocket as PAM and also interacts with residue W773, but NAM occupies the binding site a little deeper than PAM. This causes NAM to push the side chain of W773 towards helix 7, which does not form the cleft for G-protein binding<ref name="Lin"/>.

Moving from the intermediate state, a second glutamate will bind in the other lobe of the VFT. This will help close the VFT and move the CRD closer together <ref name="Seven" />. A positive allosteric modulator (PAM) or a negative allosteric modulator (NAM) will then come in and bind to mGlu2. PAM and NAM induce different conformational changes, which result in different outcomes. <scene name='90/904308/Pam/4'>PAM binds</scene> the TMD and promotes greater affinity for the binding of the G-protein. There are different types of PAMs that can bind to the TMD but this page focuses on JNJ-40411813<ref name="Lin"/>. PAM binds in a binding pocket that is created by helices 3, 5, 6, and 7 in the <scene name='90/904307/Tmd_helices/4'>TMD</scene>. Within helix 6, the hydrophobic binding is composed of W773, F776, L777, and F780. Due to spatial hindrance caused by the binding of PAM, helix 6 is shifted downward, causing reorientation of the TMD. This reorientation creates a cleft in the TMD for the G-protein to bind<ref name="Lin"/>. NAM, however, reduces the affinity for G protein binding. <scene name='90/904308/Nam_bound/2'>NAM binds</scene> to the same binding pocket as PAM and also interacts with residue W773, but NAM occupies the binding site a little deeper than PAM. This causes NAM to push the side chain of W773 towards helix 7, which does not form the cleft for G-protein binding<ref name="Lin"/>.

[[Image:PAM binding pocket correct.png |300px|right|thumb|'''Figure 4.'''PAM binding pocket. PAM, JNJ-40411813, is shown in magenta and colored by atom type, four labelled binding helices (3, 5, 6, and 7) create the binding pocket in the 7TM region for PAM binding. PAM binding promotes G-protein activation by mGLu2.]]

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@@ Line 18: / Line 18: @@
 ===Inactive State===
-A few hallmarks of the <scene name='90/904308/Inactive_structure/1'>inactive structure</scene> of mGlu2 are the <scene name='90/904307/Better_inactive_structure/3'>VFT</scene> in the open conformation, well separated <scene name='90/904307/Better_inactive_structure/2'>CRD</scene>, and distinct orientation of the 7TM. The most critical component of the inactive form is the <scene name='90/904307/Tmd_helices/4'>asymmetric TM3-TM4 interface</scene> formed by the 7 α-helices in the α and β chains of the 7TM. The inactive structure of mGlu2 is mediated mainly by helices 3 and 4 on both the α and β chains of the dimer through hydrophobic interactions. These <scene name='90/904307/Tm3-tm4_hydrophobic/2'>hydrophobic interactions</scene> between both transmembrane helices stabilize inactive conformation of mGlu2<ref name="Lin"/>.
+A few hallmarks of the <scene name='90/904308/Inactive_structure/1'>inactive structure</scene> of mGlu2 are the <scene name='90/904307/Better_inactive_structure/3'>VFT</scene> in the open conformation, well separated <scene name='90/904307/Better_inactive_structure/2'>CRD</scene>, and distinct orientation of the 7TM. The most critical component of the inactive form is the asymmetric TM3-TM4 interface formed by the 7 α-helices in the α and β chains of the 7TM. The inactive structure of mGlu2 is mediated mainly by helices 3 and 4 on both the α and β chains of the dimer through hydrophobic interactions. These <scene name='90/904307/Tm3-tm4_hydrophobic/2'>hydrophobic interactions</scene> between both transmembrane helices stabilize inactive conformation of mGlu2<ref name="Lin"/>.
 [[Image:Schematic of mGlu2.jpg|400 px|left|thumb|'''Figure 3.''' Demonstrates the conformational changes of mGlu2.]]
@@ Line 25: / Line 25: @@
 ===PAM and NAM Bound Form===
-Moving from the intermediate state, a second glutamate will bind in the other lobe of the VFT. This will help close the VFT and move the CRD closer together <ref name="Seven" />. A positive allosteric modulator (PAM) or a negative allosteric modulator (NAM) will then come in and bind to mGlu2. PAM and NAM induce different conformational changes, which result in different outcomes. <scene name='90/904308/Pam/3'>PAM binds</scene> the TMD and promotes greater affinity for the binding of the G-protein. There are different types of PAMs that can bind to the TMD but this page focuses on JNJ-40411813<ref name="Lin"/>. PAM binds in a binding pocket that is created by helices 3, 5, 6, and 7 in the <scene name='90/904307/Tmd_helices/4'>TMD</scene>. Within helix 6, the hydrophobic binding is composed of W773, F776, L777, and F780. Due to spatial hindrance caused by the binding of PAM, helix 6 is shifted downward, causing reorientation of the TMD. This reorientation creates a cleft in the TMD for the G-protein to bind<ref name="Lin"/>. NAM, however, reduces the affinity for G protein binding. <scene name='90/904308/Nam_bound/2'>NAM binds</scene> to the same binding pocket as PAM and also interacts with residue W773, but NAM occupies the binding site a little deeper than PAM. This causes NAM to push the side chain of W773 towards helix 7, which does not form the cleft for G-protein binding<ref name="Lin"/>.
+Moving from the intermediate state, a second glutamate will bind in the other lobe of the VFT. This will help close the VFT and move the CRD closer together <ref name="Seven" />. A positive allosteric modulator (PAM) or a negative allosteric modulator (NAM) will then come in and bind to mGlu2. PAM and NAM induce different conformational changes, which result in different outcomes. <scene name='90/904308/Pam/4'>PAM binds</scene> the TMD and promotes greater affinity for the binding of the G-protein. There are different types of PAMs that can bind to the TMD but this page focuses on JNJ-40411813<ref name="Lin"/>. PAM binds in a binding pocket that is created by helices 3, 5, 6, and 7 in the <scene name='90/904307/Tmd_helices/4'>TMD</scene>. Within helix 6, the hydrophobic binding is composed of W773, F776, L777, and F780. Due to spatial hindrance caused by the binding of PAM, helix 6 is shifted downward, causing reorientation of the TMD. This reorientation creates a cleft in the TMD for the G-protein to bind<ref name="Lin"/>. NAM, however, reduces the affinity for G protein binding. <scene name='90/904308/Nam_bound/2'>NAM binds</scene> to the same binding pocket as PAM and also interacts with residue W773, but NAM occupies the binding site a little deeper than PAM. This causes NAM to push the side chain of W773 towards helix 7, which does not form the cleft for G-protein binding<ref name="Lin"/>.
 [[Image:PAM binding pocket correct.png |300px|right|thumb|'''Figure 4.'''PAM binding pocket. PAM, JNJ-40411813, is shown in magenta and colored by atom type, four labelled binding helices (3, 5, 6, and 7) create the binding pocket in the 7TM region for PAM binding. PAM binding promotes G-protein activation by mGLu2.]]