Modeling of amino-terminal domains of group I metabotropic glutamate receptors: structural motifs affecting ligand selectivity.

On the basis of a new sequence alignment between the amino terminal domains of mGlu1 and mGlu5 receptor subtypes and leucine/isoleucine/valine binding protein (LIVBP), three-dimensional models of the binding sites of the two group I metabotropic glutamate receptor subtypes were constructed. The 3D-models thus obtained showed a high degree of similarity. In the region of the putative binding site, identified by Ser165 and Thr188 (mGlu1) or Ser152 and Thr175 (mGlu5), the only nonconserved residue is Pro369 (mGlu1), which is substituted by Gln356 in mGlu5. Although not directly involved in ligand binding, these residues may provide a subtle difference in the steric environment of the two active sites that may account for the observed subgroup selectivity of recently reported ligands.