Journal
SCIENCE
Volume 344, Issue 6179, Pages 58-64Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1249489
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Funding
- National Institute of General Medical Sciences (NIGMS) [U54 GM094618]
- NIH [P50 GM073197, R01 NS031373, R01 MH062646, R21 NS078262, R01 MH090192, R01 GM080403, R01 GM099842, R01 DK097376]
- International Rett Syndrome Foundation
- NHMRC (Australia)
- NARSAD
- NSF [CHE 1305874]
- National Cancer Institute [Y1-CO-1020]
- NIGMS [Y1-GM-1104]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1305874] Funding Source: National Science Foundation
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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 mGlu(1) 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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