Orthosteric and allosteric drug binding sites in the Caenorhabditis elegans mgl-2 metabotropic glutamate receptor

► Mgl-2, a Caenorhabditis elegans receptor had lower affinity for glutamate compared to rat mGluR5. ► Negative allosteric modulators were ineffective at mgl-2. ► CDPPB, an mGluR5 positive allosteric modulator, potentiated glutamate. ► The glutamate site is conserved whereas allosteric sites show evolutionary changes.