Résumé
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.