metabotropic Glutamate Receptor 5 Homo sapiens

Introduction

G-coupled protein receptors GPCR are trans-membrane proteins that are integral to cell signaling. The human genome encodes for approximately 750 GPCRS, 350 of which are known to respond to extracellular ligands.^[1]. GPCRs are divided into four major classes based on sequence similarity and transduction mechanism; Class A,B,C, and F.^[2]. Metabotropic Glutamate Receptor 5 (mGlu₅) is a class C GPCR that is involved in the G_q pathway ^[3]. mGlu₅is highly expressed in neuronal and glial cells in the central nervous system, where glutamate serves as the major neurotransmitter. When glutamate binds to the extracellular domain of mGlu₅, consisting of the Venus Fly Trap ^[4], a conformational change through the tram-membrane domains activates the coupled G-protein. This G-protein disassociates and the alpha subunit activates Phospholipase C which has the final outcome of increased neuronal activity^[2].

Structure

Overall Stucture

mGlu₅ is seen as a homodimer in vivo, with each subunit comprising three domains; extracellular, trans-membrane and cysteine-rich. The structures shown here are centered on the trans-membrane domain, comprised of seven α-helices all roughly parallel to one another ^[4]. Also displayed are Intracellular Loop (ICL) 1 forming a short α-helix, ICL3 and Extracellular Loops (ECL) 1 and 3, which lack secondary structure, and ECL2, which interacts with trans-membrane (TM) helices 1,2 and 3 and ECL 1^[4].

Key Interactions

A number of intramolecular interactions within the trans-membrane domain stabilize the inactive conformation of mGlu₅. The first of these interactions is an ionic interaction, termed the , between Lysine 665 of TM3 and Glutamate 770 of TM6. Evidence for the importance of this interaction came through a kinetic study of mutant proteins where both residues were separately mutated to alanine resulting in constitutive activity of the GPCR and its coupled pathway^[4].A second critical interaction that stabilizes the inactive conformer is a between Serine 614 of ICL1 and Arginine 668 of TM3. Similarly, when Serine 614 is mutated to alanine high levels of activity are seen in the mutant GPCR^[4]. A between Cystine 644 of TM3 and Cystine 733 of ECL2 is critical at anchoring ECL2 and is highly conserved across Class C GPCR’s^[4]. The ECL2 position, in combination with the helical bundle of the trans-membrane domain, create a that restricts entrance to the allosteric binding site within the seven trans-membrane α-helices. This restricted entrance has no effect on the natural ligand, glutamate, as it binds to the extracellular domain, but dictates potential drug targets that act through allosteric modulation^[4].

Clinical Relevance

Role in Diseases

mGlu₅ is located mainly post-synaptically and is in high abundance in the nucleus accumbens, caudate nucleus, striatum, hippocampus and cerebellar cortex ^[5].

Interactions with a Negative Allosteric Modulator

Hydrophobic Pocket Surrounding Mavoglurant

Further Hydrogen Bonding between protein and Mavoglurant