Sandbox Reserved 1702

This Sandbox is Reserved from February 28 through September 1, 2022 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1700 through Sandbox Reserved 1729.

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Metabotropic Glutamate Receptor 2Metabotropic Glutamate Receptor 2

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StructureStructure

Overall StructureOverall Structure

Cryo-EM studies of mGlu2 have yielded adequate structures that have acted as maps to aid in producing a better structural understanding of the inactive and active states of mGlu2 (Lin). The overall of the mGlu2 is composed of 3 main parts: a ligand binding , followed by a linker to the that contains 7 alpha helices (7TM) on both the alpha and beta chains that aid in the binding of the G-Protein. Class C CPCRs such as mGlu2, are activated by their ability to form dimers. MGlu2 is a homodimer which is imperative to the receptor’s ability to relay signals induced by glutamate from the extracellular domain(ECD) to its transmembrane domain(TMD). The homodimer of mGlu2 contains an alpha chain and a beta chain. Occupation of both ECDs with the agonist, glutamate, is necessary for a fully active mGlu2. However, only one chain in the dimer is responsible for activation of the G-protein, this suggests an asymmetrical signal transduction mechanism for mGlu2.

InactiveInactive

A few hallmarks of the inactive structure of mGlu2 are the in the , well separated , and distinct orientation of the 7 Transmembrane Domains (7TM). Perhaps the most critical component of the inactive form is the formed by both of the 7 alpha helices in the alpha and beta chains in the transmembrane domain. The transmembrane domain is mediated mainly by helix IV on the alpha chain and helix lll on the beta chain of the dimer through hydrophobic interactions. These between both transmembrane helices stabilize inactive conformation of mGlu2.

ActiveActive

Upon binding of the PAM, helix VI is shifted downward in the transmembrane domain. This downward shift induces a reorientation of the transmembrane domain from its original TM3-TM4 asymmetric dimer interface in the inactive form to now a TM6-TM6 asymmetric dimer interface. The downward shift of helix VI 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 transmembrane domain that stabilize the inactive form (2) positions intracellular loops of the helices in the transmembrane domain to assist in the binding and recognitions of the G-Protein.