6YK5

Structure of the AMPA receptor GluA2o ligand-binding domain (S1S2J) in complex with the compound (S)-1-(2'-Amino-2'-carboxyethyl)-5,7-dihydrofuro[3,4-d]- pyrimidine-2,4(1H,3H)-dione at resolution 1.15A

Summary for 6YK5

• Entry DOI: 10.2210/pdb6yk5/pdb
• Descriptor: Glutamate receptor 2, GLYCEROL, SULFATE ION, ... (7 entities in total)
• Functional Keywords: ionotropic glutamate receptor, glua2o ligand-binding domain, bicyclic pyrimidinedione analogue, membrane protein
• Biological source: Rattus norvegicus (Norway Rat); More
• Total number of polymer chains: 1
• Total formula weight: 30507.08

Authors

Frydenvang, K.,Kastrup, J.S. (deposition date: 2020-04-05, release date: 2020-06-03, Last modification date: 2024-11-13)

Primary citation

Frydenvang, K.,Pickering, D.S.,Kshirsagar, G.U.,Chemi, G.,Gemma, S.,Sprogoe, D.,Kærn, A.M.,Brogi, S.,Campiani, G.,Butini, S.,Kastrup, J.S.
Ionotropic Glutamate Receptor GluA2 in Complex with Bicyclic Pyrimidinedione-Based Compounds: When Small Compound Modifications Have Distinct Effects on Binding Interactions.
Acs Chem Neurosci, 11:1791-1800, 2020

PubMed Abstract: ()-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA) receptors comprise an important class of ionotropic glutamate receptors activated by glutamate in the central nervous system. These receptors have been shown to be involved in brain diseases, for example, Alzheimer's disease and epilepsy. To understand the functional role of AMPA receptors at the molecular level and their potential as targets for drugs, development of tool compounds is essential. We have previously reported the synthesis of six bicyclic pyrimidinedione-based analogues of willardiine with differences limited to the pyrimidinedione-fused five-membered rings. Despite minor molecular differences, we observed >500-fold difference in binding affinity of the compounds at full-length GluA2. Here, we report binding affinities and the binding mode of these compounds at the ligand-binding domain of GluA2 using X-ray crystallography. The structures revealed similar binding modes, with distinct differences in the interaction between GluA2 and the compounds. The methylene () and sulfur () containing compounds showed the greatest binding affinities. Changing the dihydrothiophene () into pyrrolidine (), -methyl pyrrolidine (), or dihydrofuran () induced flexibility in the position of a binding-site water molecule and changes in the hydrogen-bonding network between compound, water, and GluA2. This might be essential for explaining the reduced binding affinity of these compounds. The weakest binding affinity was observed when the aliphatic oxygen containing dihydrofuran () was changed into an aromatic furan system (). Molecular docking studies revealed two possible orientations of , whereas only one binding mode was observed for the other analogues. This could likely contribute to the weakest binding affinity of at GluA2.

PubMed: 32437601
DOI: 10.1021/acschemneuro.0c00195

Experimental method

X-RAY DIFFRACTION (1.15 Å)