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

Chen, Qi; Ho, Joseph D.; Ashok, Sheela; Vargas, Michelle C.; Wang, Jing; Atwell, Shane; Bures, Mark; Schkeryantz, Jeffery M.; Monn, James A.; Hao, Junliang

doi:10.1021/acs.jmedchem.8b01120

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

Journal Article · 25 October 2018 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.8b01120 · OSTI ID:1506531

Chen, Qi ^[1]; Ho, Joseph D. ^[1]; Ashok, Sheela ^[1]; Vargas, Michelle C. ^[1]; Wang, Jing ^[1]; Atwell, Shane ^[1]; Bures, Mark ^[1]; Schkeryantz, Jeffery M. ^[1]; Monn, James A. ^[1];

^[1]

Eli Lilly and Company, Indianapolis, IN (United States)

(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. Herein, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Eli Lilly and Company; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1506531

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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