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

Huixian Wu, Chong Wang, Karen Joan Gregory, Gye Won Han, Hyekyung Plumley Cho, Yan Xia, Colleen M Niswender, Vsevolod Katritch, Jens Meiler, Vadim Cherezov, Peter Jeffrey Conn, Raymond C Stevens

Research output: Contribution to journalArticleResearchpeer-review

375 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)58 - 64
Number of pages7
JournalScience
Volume344
Issue number6179
DOIs
Publication statusPublished - 2014

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