Structural highlights
Function
[GRM8_HUMAN] G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity.[1]
Publication Abstract from PubMed
(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 co-crystal 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.
Structural Basis for (S)-3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu8 Receptor.,Chen Q, Ho JD, Ashok S, Vargas MC, Wang J, Atwell S, Bures M, Schkeryantz JM, Monn JA, Hao J J Med Chem. 2018 Oct 26. doi: 10.1021/acs.jmedchem.8b01120. PMID:30365309[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR Jr, Johnson BG, Schoepp DD, Belagaje RM. Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells. Brain Res Mol Brain Res. 1998 Jan;53(1-2):88-97. PMID:9473604
- ↑ Chen Q, Ho JD, Ashok S, Vargas MC, Wang J, Atwell S, Bures M, Schkeryantz JM, Monn JA, Hao J. Structural Basis for (S)-3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu8 Receptor. J Med Chem. 2018 Oct 26. doi: 10.1021/acs.jmedchem.8b01120. PMID:30365309 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01120
