| Autor: |
Chen Q, Ho JD, Ashok S, Vargas MC, Wang J, Atwell S, Bures M, Schkeryantz JM, Monn JA, Hao J |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2018 Nov 21; Vol. 61 (22), pp. 10040-10052. Date of Electronic Publication: 2018 Nov 07. |
| DOI: |
10.1021/acs.jmedchem.8b01120 |
| Abstrakt: |
( S)-3,4-Dicarboxyphenylglycine (DCPG) was first reported in 2001 as a potent orthosteric agonist with high subtype selectivity for the mGlu 8 receptor, but the structural basis for its high selectivity is not well understood. We have solved a cocrystal structure of recombinant human mGlu 8 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 mGlu 1 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 mGlu 8 ATD crystal structure were explored to rationalize ( S)-DCPG's high mGlu 8 receptor subtype selectivity. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
