Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator

The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein-coupled receptors (GPCRs). We determined the 2.8 A resolution structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator FITM. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs, but is more restricted compared to most other GPCRs. We observed a parallel 7TM dimer, mediated by cholesterols, suggesting that signaling initiated by glutamate’s interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights on the allosteric modulation and activation mechanism of class C GPCRs.