title: Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.
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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Gregory
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002784:Cholesterol; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C560416:4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide; D001549:Benzamides; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; D002784:Cholesterol