title: Three-dimensional model of the extracellular domain of the type 4a metabotropic glutamate receptor: new insights into the activation process.
abstract: Metabotropic glutamate receptors (mGluRs) belong to the family 3 of G-protein-coupled receptors. On these proteins, agonist binding on the extracellular domain leads to conformational changes in the 7-transmembrane domains required for G-protein activation. To elucidate the structural features that might be responsible for such an activation mechanism, we have generated models of the amino terminal domain (ATD) of type 4 mGluR (mGlu4R). The fold recognition search allowed the identification of three hits with a low sequence identity, but with high secondary structure conservation: leucine isoleucine valine-binding protein (LIVBP) and leucine-binding protein (LBP) as already known, and acetamide-binding protein (AmiC). These proteins are characterized by a bilobate structure in an open state for LIVBP/LBP and a closed state for AmiC, with ligand binding in the cleft. Models for both open and closed forms of mGlu4R ATD have been generated. ACPT-I (1-aminocyclopentane 1,3,4-tricarboxylic acid), a selective agonist, has been docked in the two models. In the open form, ACPT-I is only bound to lobe I through interactions with Lys74, Arg78, Ser159, and Thr182. In the closed form, ACPT-I is trapped between both lobes with additional binding to Tyr230, Asp312, Ser313, and Lys317 from lobe II. These results support the hypothesis that mGluR agonists bind a closed form of the ATDs, suggesting that such a conformation of the binding domain corresponds to the active conformation.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601-CNRS, Université René Descartes-Paris V, France.
authors.forename: A S
authors.initials: AS
authors.lastname: Bessis
authors.forename: H O
authors.initials: HO
authors.lastname: Bertrand
authors.forename: T
authors.initials: T
authors.lastname: Galvez
authors.forename: C
authors.initials: C
authors.lastname: De Colle
authors.forename: J P
authors.initials: JP
authors.lastname: Pin
authors.forename: F
authors.initials: F
authors.lastname: Acher
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D029968:Escherichia coli Proteins; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D033902:Periplasmic Binding Proteins; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D012984:Software
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D008024:Ligands; C024913:LivK protein, E coli; D033902:Periplasmic Binding Proteins; D018094:Receptors, Metabotropic Glutamate; C028332:leucine-isoleucine-valine binding protein, bacteria; C070135:AmiC protein, Pseudomonas aeruginosa; C108823:metabotropic glutamate receptor 4