6e5v
human mGlu8 receptor amino terminal domain in complex with (S)-3,4-Dicarboxyphenylglycine (DCPG)human mGlu8 receptor amino terminal domain in complex with (S)-3,4-Dicarboxyphenylglycine (DCPG)
Structural highlights
FunctionGRM8_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. See AlsoReferences
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