Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator

Science  DOI: 10.1126/science.1249489

Abstract

he excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which                        are class C G protein-coupled receptors (GPCRs). We determined the 2.8 Å resolution structure of the human mGlu₁ receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator FITM. The modulator binding site partially                        overlaps with the orthosteric binding sites of class A GPCRs, but is more restricted compared to most other GPCRs. We observed                        a parallel 7TM dimer, mediated by cholesterols, suggesting 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 on the allosteric modulation and activation mechanism                        of class C GPCRs.                    

full text:

http://www.sciencemag.org/content/early/2014/03/05/science.1249489.full