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 (mGlu 4 R). 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 mGlu 4 R 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.