Nature (2014) doi:10.1038/nature13396  Received20  January 2014 Accepted22  April 2014 Published  online06 July 2014

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Abstract

Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.

a, b, Ribbon representation of mGlu₅ in rainbow colouration (N terminus, blue; C terminus, red) viewed parallel to the membrane and from the extracellular space, respectively. Mavoglurant is represented in translucent stick representat…