Sandbox Reserved 1703: Difference between revisions

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

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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: a ligand binding <scene name='90/904307/Better_inactive_structure/3'>Venus Fly Trap Domain (VFT)</scene>, followed by a <scene name='90/904307/Better_inactive_structure/2'>Cysteine Rich Domain (CRD)</scene> linker to the <scene name='90/904307/Better_inactive_structure/4'>Transmembrane Domain</scene> that contains 7 α-helices (7TM) on both the α and β chains. The VFT and CRD are located in the intracellular domain (ICD), while the TMD is located in the extracellular domain (ECD) (Figure 2). The TMD aids in the binding of the G-protein.
-[[Image:Domains of mGlu2.jpg|200 px|right|thumb|'''Figure 2.'''Show the regions of mGlu2.]]
+[[Image:Domains of mGlu2.jpg|250 px|right|thumb|'''Figure 2.'''Show the regions of mGlu2.]]
 mGlu2 is a [https://en.wikipedia.org/wiki/Protein_dimer homodimer]. Dimerization of mGlu2 is required to relay glutamate binding from the ECD to its TMD. The homodimer of mGlu2 contains an <scene name='90/904308/Alphaandbetachain/8'>α-chain and a β-chain</scene>. Occupation of both ECDs with the agonist, glutamate, is necessary for a fully active mGlu2<ref name="Du">Du, Juan, et al. “Structures of Human mglu2 and mglu7 Homo- and Heterodimers.” Nature News, Nature Publishing Group, 16 June 2021, https://www.nature.com/articles/s41586-021-03641-w.></ref>. However, only one chain in the dimer is responsible for activation of the G-protein, this suggests an asymmetrical signal transduction mechanism for mGlu2<ref name="Lin"/>.
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 ===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
-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 III, V, VI, VII 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 VII<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 |250px|right|thumb|'''Figure 4.'''PAM binding pocket. PAM, JNJ-40411813, is shown in magenta and colored by atom type, four labelled binding helices (III, V, VI, and VII) create the binding pocket in the 7TM region for PAM binding. PAM binding promotes G-protein activation by mGLu2.]]
+[[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.]]
 ===Active State===
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 ====G-Protein Recognition====
-Transition to the active state also reorients helix lll in both monomers to enable binding to the G-protein: Yet only one chain is required for full receptor activation. The intracellular region of helix lll contributes the main interactions with the alpha subunit of the G-protein. Intracellular Loop 2 also builds a polar interaction network with the G-protein through its ionic interactions with the <scene name='90/904308/Binding_recognition_site/2'> α-subunit</scene> of the G-protein. Lastly, mGlu2 residue E666 forms a salt bridge with residue (R32) on the α-subunit which further destabilizes the inactive conformation<ref name="Lin"/>.
+Transition to the active state also reorients helix 3 in both monomers to enable binding to the G-protein: Yet only one chain is required for full receptor activation. The intracellular region of helix 3 contributes the main interactions with the α-subunit of the G-protein. Intracellular Loop 2 also builds a polar interaction network with the G-protein through its ionic interactions with the <scene name='90/904308/Binding_recognition_site/2'> α-subunit</scene> of the G-protein. Lastly, mGlu2 residue E666 forms a salt bridge with residue (R32) on the α-subunit which further destabilizes the inactive conformation<ref name="Lin"/>.
 ====G-protein Binding====