8X0E

Human FL Metabotropic glutamate receptor 5, mGlu5-5M with agonist and PAM, W785A mutant

Summary for 8X0E

• Entry DOI: 10.2210/pdb8x0e/pdb
• EMDB information: 37973 37974 37975 37976 37977 37978
• Descriptor: Metabotropic glutamate receptor 5, 2-acetamido-2-deoxy-beta-D-glucopyranose, (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID (3 entities in total)
• Functional Keywords: g-protein coupled receptors, signal transduction, metabotropic glutamate receptor, agonist, active state, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 188059.43

Authors

Vinothkumar, K.R.,Lebon, G.,Cannone, G. (deposition date: 2023-11-04, release date: 2024-11-06, Last modification date: 2025-01-29)

Primary citation

Cannone, G.,Berto, L.,Malhaire, F.,Ferguson, G.,Fouillen, A.,Balor, S.,Font-Ingles, J.,Llebaria, A.,Goudet, C.,Kotecha, A.,K R, V.,Lebon, G.
Conformational diversity in class C GPCR positive allosteric modulation.
Nat Commun, 16:619-619, 2025

PubMed Abstract: The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state.

PubMed: 39805839
DOI: 10.1038/s41467-024-55439-9

Experimental method

ELECTRON MICROSCOPY (3.4 Å)