8JD3

Cryo-EM structure of Gi1-bound mGlu2-mGlu3 heterodimer

Summary for 8JD3

• Entry DOI: 10.2210/pdb8jd3/pdb
• EMDB information: 36174
• Descriptor: Metabotropic glutamate receptor 2, Metabotropic glutamate receptor 3, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (9 entities in total)
• Functional Keywords: complex structure, mglu2-mglu3 heterodimer with gi protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 286005.23

Authors

Wang, X.,Wang, M.,Xu, T.,Feng, Y.,Han, S.,Lin, S.,Zhao, Q.,Wu, B. (deposition date: 2023-05-12, release date: 2023-06-21, Last modification date: 2023-10-18)

Primary citation

Wang, X.,Wang, M.,Xu, T.,Feng, Y.,Shao, Q.,Han, S.,Chu, X.,Xu, Y.,Lin, S.,Zhao, Q.,Wu, B.
Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.
Cell Res., 33:762-774, 2023

PubMed Abstract: Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.

PubMed: 37286794
DOI: 10.1038/s41422-023-00830-2

Experimental method

ELECTRON MICROSCOPY (3.3 Å)