Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptor dimers that can adopt at least two main conformations, the inactive resting (R) and active (A) states, which are in dynamic equilibrium. Each subunit of the dimer has a large extracellular domain and is composed of the Venus flytrap domain (VFT), which contains the orthosteric binding site for glutamate, and a cysteine-rich domain (CRD). The CRD links the VFT to the 7-transmembrane domain (7TM), which couples to G protein. Using electron cryomicroscopy, X-ray crystallography and photopharmacology, we investigated the structural basis of mGlu5 activation mechanism. The resting conformation of mGlu5 receptor dimer bound to orthosteric antagonist LY341495 displays VFT's in the open and resting conformation, keeping the 7TM domains apart from each other but can still activate G protein upon positive allosteric modulation. L-glutamate stabilises the resting conformation that leads to more compact closed and active agonist bound state. A common binding site is observed in the membrane domain for both positive and negative allosteric modulators of mGlu5. The structural and biochemical studies show that different mGlu5 receptor conformations are stabilized by ligands in the ECD and 7TM can regulate G protein signalling.