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Vol. 60, Issue 5, 944-954, November 2001
Pharma Division, Preclinical Research, Nervous System Diseases, F. Hoffmann-La Roche Ltd., Basel, Switzerland
Metabotropic glutamate (mGlu) receptors are a family of
G-protein-coupled receptors that play central roles as modulators of
both glutamatergic and other major neurotransmitter systems in CNS.
Using molecular modeling, site-directed mutagenesis,
[3H]LY354740 binding, [35S]GTP
S binding,
and activation of GIRK current, we have been able to identify residues
crucial for the binding of LY354740 and glutamate to rat mGlu2
receptors. Several of the crucial residues located in the binding site
(Arg-57, Tyr-144, Tyr-216, Asp-295) have not been identified
previously. We propose that the -carboxyl group of LY354740 forms
H-bonds to Arg-57, whereas the 
-carboxyl group forms an H-bond with
the hydroxyl group of Ser-145. The -amino group of LY354740 forms
H-bonds to Asp-295 and to the side-chain hydroxyl group of Thr-168. In
addition, Tyr-144 may establish a hydrophobic (C-H/
)-interaction
with the bicyclo-hexane ring of LY354740. Furthermore, the mutation of
residues Ser-148 and Arg-183, which are too remote for a direct
interaction, affected the ligand affinity dramatically. These results
suggest that Ser-148 and Arg-183 may be important for the 3D structure
and/or are involved in closure of the domain. Finally, Asp-146, which
is also remote from the binding site, was shown to be involved in the
differential binding affinity of [3H]LY354740 for mGlu2
versus mGlu3 receptors. All the mGlu receptors except mGlu2 are
activated by Ca2+ and have serine instead of aspartic acid
at this position, which suggests a critical role of this aspartic acid
residue in the binding properties of this unique receptor.
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