TY - JOUR
T1 - Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator
AU - Wu, Huixian
AU - Wang, Chong
AU - Gregory, Karen Joan
AU - Han, Gye Won
AU - Cho, Hyekyung Plumley
AU - Xia, Yan
AU - Niswender, Colleen M
AU - Katritch, Vsevolod
AU - Meiler, Jens
AU - Cherezov, Vadim
AU - Conn, Peter Jeffrey
AU - Stevens, Raymond C
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.sciencemag.org/content/344/6179/58.full.pdf
U2 - 10.1126/science.1249489
DO - 10.1126/science.1249489
M3 - Article
SN - 0036-8075
VL - 344
SP - 58
EP - 64
JO - Science
JF - Science
IS - 6179
ER -