Sandbox Reserved 1703: Difference between revisions

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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA, Jaime Prilusky, Ashley R. Wilkinson, R. Jeremy Johnson

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 =Metabotropic Glutamate Receptor 2=
-<StructureSection load='' size='350' frame='true' side='right' caption='Fully Active mGlu2 with G-Protein Bound' scene='90/904307/Main_active_image/2'>
+<StructureSection load='' size='350' frame='true' side='right' caption='Fully Active mGlu2 with G-Protein Bound (PDB: [[7mts]])' scene='90/904307/Main_active_image/2'>
 ==Introduction==
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 ===Overall Structure===
-[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-EM] studies of mGlu2 have yielded adequate structural maps of mGlu2 in various activation states. These maps provided clearer understanding of the conformational changes between the inactive and active states of mGlu2<ref name="Lin" />. The conformational changes allow mGlu2 to move from an inactive <scene name='90/904307/Inactive_to_active_morph/1'>open to a closed</scene> active conformation. The overall <scene name='90/904307/Inactive_structure/1'>structure</scene> of the mGlu2 is composed of 3 main parts. First, a ligand binding <scene name='90/904307/Better_inactive_structure/3'>Venus Fly Trap Domain(VFT)</scene>, that binds two glutamates which are the agonists. This is followed by a <scene name='90/904307/Better_inactive_structure/2'>Cysteine Rich Domain(CRD)</scene> that links the VFT to the TMD. The CRD is helpful in relaying signals for conformational changes in the TMD induced by agonist binding in the VFT<ref name="Lin" />. The VFT and CRD are located in the intracellular domain(ICD), while the TMD is located in the ECD (Figure 2). Finally the<scene name='90/904307/Better_inactive_structure/4'>TMD</scene> contains 7 α-helices (7TM) on both the α and β chains. The TMD aids in the binding of the G-protein.
+[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-EM] studies of mGlu2 have yielded adequate structural maps of mGlu2 in various activation states. These maps provided clearer understanding of the conformational changes between the inactive and active states of mGlu2<ref name="Lin" />. The conformational changes allow mGlu2 to move from an inactive <scene name='90/904307/Inactive_to_active_morph/1'>open to a closed</scene> active conformation. The overall <scene name='90/904307/Inactive_structure/1'>structure</scene> of the mGlu2 is composed of 3 main parts. First, a ligand binding <scene name='90/904307/Better_inactive_structure/3'>Venus Fly Trap Domain(VFT)</scene>, that binds two glutamates which are the agonists. This is followed by a <scene name='90/904307/Better_inactive_structure/2'>Cysteine Rich Domain(CRD)</scene> that links the VFT to the TMD. The CRD is helpful in relaying signals for conformational changes in the TMD induced by agonist binding in the VFT<ref name="Lin" />. The VFT and CRD are located in the intracellular domain(ICD), while the TMD is located in the ECD (Figure 2). Finally the <scene name='90/904307/Better_inactive_structure/4'>TMD</scene> contains 7 α-helices (7TM) on both the α and β chains. The TMD aids in the binding of the G-protein.
 [[Image:Domains of mGlu2.jpg|250 px|right|thumb|'''Figure 2.'''Shown above the line is the intracellular region containing the VFT and CRD. Shown below the line is the extracellular region containing the TMD of mGlu2.]]
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 ===Intermediate Form===
-No Cryo-EM structures are currently available for the intermediate form, but it is an important state for the full activation of mGlu2. While in the intermediate form, glutamate, the agonist of mGlu2, binds the agonist binding site. The <scene name='90/904308/Agonist_binding_site/4'>Agonist Binding Site</scene> is formed by both lobes of the VFT. To stabilize the intermediate state, one glutamate will bind, which will cause the closure of one VFT <ref name="Seven" />. mGlu2 will still remain inactive after a glutamate is bound. The binding of glutamate promotes signaling down the receptor <ref name="Lin" />.
+No Cryo-EM structures are currently available for the intermediate form, but it is an important state for the full activation of mGlu2. While in the intermediate form, glutamate binds the agonist binding site. The <scene name='90/904308/Agonist_binding_site/4'>Agonist Binding Site</scene> is formed by both lobes of the VFT. To stabilize the intermediate state, one glutamate will bind, which will cause the closure of one lobe of the VFT <ref name="Seven" />. mGlu2 will still remain inactive after a glutamate is bound. The binding of glutamate promotes signaling down the receptor <ref name="Lin" />.
 ===PAM and NAM Bound Form===
-Moving from the intermediate state, a second glutamate will bind in the other 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 FINISH
+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. 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. 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<ref name="Lin"/>.
-induce different conformational changes, which result in different outcomes. <scene name='90/904308/Pam/3'>PAM binds</scene> to the receptor, induces conformational changes, which helps to promote greater affinity for G protein binding. PAM binds in a binding pocket that is created by helices 3, 5, 6, 7 in the <scene name='90/904307/Tmd_helices/4'>TMD</scene>. Within helix VI, the hydrophobic binding is composed of W773, F776, L777, and F780. Due to spatial hindrance caused by the binding of PAM, helix VI is shifted downward, causing conformational changes that increase G-protein binding affinity. 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<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.]]