Glutamate is the major excitatory neurotransmitter in the central nervous system. The metabotropic glutamate (mGlu) receptors can be divided into three groups on the basis of their sequence similarity. The mGlu5 is abundant through-out the cortex, hippocampus, striatum, and caudate nucleus, which involved in emotion, motivation and cognition.
Here, we reported that the structure was solved by molecular replacement with one copy of the receptor in the asymmetric unit. Structure analysis shows that mGlu receptors have an unusual structure comprising a large extracellular domain consisting of the VFT, which binds glutamate and a cysteine-rich domain (CRD). The most striking difference between mGlu5 and other receptor is the position of TM5.
As mGlu5 is a promising therapeutic target and negative allosteric modulators (NAMs) which reduce mGlu5 receptor activation are undergoing clinical trials for the treatment of fragile X syndrome, depression, anxiety.
This work provides a detailed interpretation of the core domain of a class C GPCR, adding the extra-cellular domain structures. The mGlu5 receptor structure also increases our understanding of the mechanism of action of allosteric modulators for metabotropic receptors and will enable the design of modulators. There is a great promise in the treatment of severe neuropsychiatric disorders.