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Niswender Laboratory

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

AUTHORS

Wu HHuixian , Wang CChong , Gregory KJKaren J , Han GWGye Won , Cho HPHyekyung P , Xia YYan , Niswender CMColleen M , Katritch VVsevolod , Meiler JJens , Cherezov VVadim , Conn PJP Jeffrey , Stevens RCRaymond C . Science (New York, N.Y.). 2014 3 6; 344(6179). 58-64

ABSTRACT

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 structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests 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 about the allosteric modulation and activation mechanism of class C GPCRs.

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