Sandbox Reserved 1703: Difference between revisions

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"/>.