Three-dimensional model of the extracellular domain of the type 4a metabotropic glutamate receptor: new insights into the activation process

Protein Sci. 2000 Nov;9(11):2200-9. doi: 10.1110/ps.9.11.2200.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Binding Sites
  • Carrier Proteins / chemistry
  • Crystallography, X-Ray
  • Databases, Factual
  • Escherichia coli Proteins*
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Periplasmic Binding Proteins*
  • Protein Binding
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Metabotropic Glutamate / chemistry*
  • Sequence Homology, Amino Acid
  • Software

Substances

  • Bacterial Proteins
  • Carrier Proteins
  • Escherichia coli Proteins
  • Ligands
  • LivK protein, E coli
  • Periplasmic Binding Proteins
  • Receptors, Metabotropic Glutamate
  • leucine-isoleucine-valine binding protein, bacteria
  • AmiC protein, Pseudomonas aeruginosa
  • metabotropic glutamate receptor 4