The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system1. These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties2-4. Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.
International Workshop of 3D Molecular Imaging by Cryo-Electron Microscopy, Third K. H. Kuo Summer School of Electron Microscopy and Crystallography in 2010.
International Workshop of Advanced Image Processing of Cryo-Electron Microscopy, 2013
Get acquainted with Cryo-Electron Microscopy: First Chinese Workshop for Structural Biologists, 2015
International Workshop of Advanced Image Processing of Cryo-Electron Microscopy, 2015
Instutions
Instutions
Institute of Biophysics, Chinese Academy of Sciences
The Scripps Research Institute
Max Planck Institute of Biochemistry
Database
Database
National Center for Biotechnology Information(NCBI)
Protein Data Bank
The Electron Microscopy Data Bank
ExPASy Proteomics Server
Pfam
3D EM
3DEM
Tools and Softwars
Tools and Softwars
CCP4
CCP-EM
MOLE 2.0 (characterization of channels and pores in protein complex)