jm8b01120_si_005.pdb (292.02 kB)

Structural Basis for (S)‑3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu8 Receptor

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posted on 26.10.2018, 00:00 by Qi Chen, Joseph D. Ho, Sheela Ashok, Michelle C. Vargas, Jing Wang, Shane Atwell, Mark Bures, Jeffery M. Schkeryantz, James A. Monn, Junliang Hao
(S)-3,4-Dicarboxyphenylglycine (DCPG) was first reported in 2001 as a potent orthosteric agonist with high subtype selectivity for the mGlu8 receptor, but the structural basis for its high selectivity is not well understood. We have solved a cocrystal structure of recombinant human mGlu8 amino terminal domain (ATD) protein bound to (S)-DCPG, which possesses the largest lobe opening angle observed to date among known agonist-bound mGlu ATD crystal structures. The binding conformation of (S)-DCPG observed in the crystal structure is significantly different from that in the homology model built from an l-glutamate-bound rat mGlu1 ATD crystal structure, which has a smaller lobe opening angle. This highlights the importance of considering various lobe opening angles when modeling mGlu ATD–ligand complex. New homology models of other mGlu receptors based on the (S)-DCPG-bound mGlu8 ATD crystal structure were explored to rationalize (S)-DCPG’s high mGlu8 receptor subtype selectivity.