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=Metabotropic Glutamate Receptor 2=

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/9'>asymmetric TM3-TM4 interface</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"/>.  

The downward shift of helix 6, caused by PAM binding, induces a reorientation of the TMD from its original TM3-TM4 asymmetric dimer interface in the inactive form to an <scene name='90/904308/Active_7_tm_transparent/1'>asymmetric TM6-TM6 interface</scene>. The downward shift of helix 6 is crucial for the receptor’s transformation from the inactive to the active form for 2 main reasons: (1) reorientation breaks key interactions in the TMD that stabilize the inactive form and (2) repositioning <scene name='90/904308/Active_structure/7'>intracellular loops</scene> of in the TMD to assist in the binding and recognitions of the <scene name='90/904308/G-protein/1'>G-Protein</scene>. The G-protein is made up of three subunits: <scene name='90/904308/Alpha_subunit/1'>α-subunit</scene>, <scene name='90/904308/Beta_subunit/1'>β-subunit</scene>, and a <scene name='90/904308/Gamma_subunit/1'>γ-subunit</scene>.

The PAM induced downward shift of helix 6 coupled with the reorientation of the transmembrane domain to a TM6-TM6 asymmetric interface, opens up a cleft on the intracellular surface of the receptor. This cleft allows a <scene name='90/904308/Hook_region/2'>hook-like region</scene>, from terminal 4 residues of the α-subunit of the G-protein to move in adjacent to helix 4 in the TMD. Within this interaction, <scene name='90/904308/Hook_region_recognition/2'>C351</scene> on the hook participates in hydrophobic interactions with ICL2 and helix 4. These interactions allow the C-terminal region of the G-protein α-subunit to bind in the cleft formed by ICL2 and residues on helix 4<ref name="Lin" />.The receptor is now <scene name='90/904307/Main_active_image/4'>fully active</scene> with the dimer coupled only to one G-protein. The VFT is in the closed conformation and the TMD helices are also reoriented in both monomers to form an asymmetric dimer interface. These interactions allow the G-protein to bind which causes mGlu2 to be fully active. Now that mGlu2 is active it can regulate different signaling transductions in the cell<ref name="Lin"/>.