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

Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC
Science. 2014 344 (6179): 58-64

PMID: 24603153 · PMCID: PMC3991565 · DOI:10.1126/science.1249489

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.

MeSH Terms (20)

Allosteric Regulation Allosteric Site Amino Acid Sequence Benzamides Binding Sites Cholesterol Crystallography, X-Ray Humans Hydrophobic and Hydrophilic Interactions Ligands Models, Molecular Molecular Sequence Data Mutation Protein Conformation Protein Multimerization Protein Structure, Secondary Protein Structure, Tertiary Receptors, Metabotropic Glutamate Structure-Activity Relationship Thiazoles

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