No abstract

No abstract

The metabotropic glutamate receptors (mGlus) are involved in modulation of synaptic transmission and neuronal excitability in the central nervous system 1 . These receptors likely exist as both homo-and heterodimers with unique pharmacological and functional properties 2-4 . Here we report four cryo-electron microscopy structures of the human mGlus, including inactive mGlu2 and mGlu7 homodimers, agonist/PAM-bound mGlu2 homodimer, and inactive mGlu2-7 heterodimer. A subtype-dependent dimerization mode of mGlus was observed, as a unique dimer interface mediated by helix IV important to limit receptor activity exists in the inactive mGlu2 structure only. The structures provide molecular details of inter-and intrasubunit conformational changes that are required for receptor activation, which distinguish class C G-proteincoupled receptors (GPCRs) from classes A and B receptors. Furthermore, the mGlu2-7 heterodimer structure and functional studies suggest that the mGlu7 subunit plays 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.The mGlus contain a large extracellular domain (ECD) composed of the Venus flytrap (VFT) domain that binds agonist and a cysteine-rich domain (CRD) connected to a seven-helical transmembrane domain (TMD) responsible for G protein coupling 4 . It has been acknowledged that homodimerization is mandatory for the function of the mGlus, making them complex allosteric proteins with two subunits influencing each other 3 . In addition, there is increasing evidence suggesting that different mGlu subunits can associate to form multiple types of heterodimers, adding complexity of function modulation in this receptor family 2,4 . However, conformational difference between the mGlu homo-and heterodimerization and how these dimers control mGlu function remain unclear. Thus, we performed single-particle

G-protein-coupled receptors (GPCRs) have central roles in intercellular communication1,2. Structural studies have revealed how GPCRs can activate G proteins. However, whether this mechanism is conserved among all classes of GPCR remains unknown. Here we report the structure of the class-C heterodimeric GABAB receptor, which is activated by the inhibitory transmitter GABA, in its active form complexed with Gi1 protein. We found that a single G protein interacts with the GB2 subunit of the GABAB receptor at a site that mainly involves intracellular loop 2 on the side of the transmembrane domain. This is in contrast to the G protein binding in a central cavity, as has been observed with other classes of GPCR. This binding mode results from the active form of the transmembrane domain of this GABAB receptor being different from that of other GPCRs, as it shows no outside movement of transmembrane helix 6. Our work also provides details of the inter- and intra-subunit changes that link agonist binding to G-protein activation in this heterodimeric complex.