4OR2

Human class C G protein-coupled metabotropic glutamate receptor 1 in complex with a negative allosteric modulator

Summary for 4OR2

• Entry DOI: 10.2210/pdb4or2/pdb
• Descriptor: Soluble cytochrome b562, Metabotropic glutamate receptor 1, 4-fluoro-N-methyl-N-{4-[6-(propan-2-ylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl}benzamide, CHOLESTEROL, ... (7 entities in total)
• Functional Keywords: human metabotropic glutamate receptor 1, allosteric modulator, novel protein engineering, gpcr network, membrane protein, psi-biology, structural genomics, gpcr, membrane, signaling protein
• Biological source: Escherichia coli (human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : Q13255
• Total number of polymer chains: 2
• Total formula weight: 91114.54

Authors

Wu, H.,Wang, C.,Gregory, K.J.,Han, G.W.,Cho, H.P.,Xia, Y.,Niswender, C.M.,Katritch, V.,Cherezov, V.,Conn, P.J.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2014-02-10, release date: 2014-03-19, Last modification date: 2024-04-03)

Primary citation

Wu, H.,Wang, C.,Gregory, K.J.,Han, G.W.,Cho, H.P.,Xia, Y.,Niswender, C.M.,Katritch, V.,Meiler, J.,Cherezov, V.,Conn, P.J.,Stevens, R.C.
Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator
Science, 344:58-64, 2014

PubMed 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.

PubMed: 24603153
DOI: 10.1126/science.1249489

Experimental method

X-RAY DIFFRACTION (2.8 Å)