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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Introduction

Structure

Overall 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.

Inactive

A few hallmarks of the inactive structure of mGlu2 are the Venus FlyTrap Domain in the open conformation, well separated Cysteine-Rich Domains, 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 hydrophobic interactions between both transmembrane helices stabilize inactive conformation of mGlu2.

Figure 2. Hydrophobic interactions of transmembrane helices III and IV that stabilize the inactive form of mGlu2.

Positive Allosteric Modulator(PAM) Bound

Negative Allosteric Modulator(NAM) Bound

Active

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.

Figure 4. The hook-like region is made up of the last 4 residues on the alpha subunit of the G-protein. Residue C351 hydrophobically interacts with intracellular loop 2 and helix IV. Due to these interactions, the G-protein is able to bind to a shallow groove formed by intracellular loops 2 and 3.

Clinical Relevance

References

1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644