6ZYU

Structure of the GluA2 ligand-binding domain (L483Y-N754S) in complex with glutamate and BPAM549

Summary for 6ZYU

• Entry DOI: 10.2210/pdb6zyu/pdb
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, ZINC ION, CACODYLATE ION, ... (10 entities in total)
• Functional Keywords: glua2-lbd, glua2-s1s2j, ampa receptor, ligand-binding domain, positive allosteric modulator, membrane protein, l483y, n754s, signaling protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 3
• Total formula weight: 91473.65

Authors

Dorosz, J.,Christensen, K.M.,Kastrup, J.S. (deposition date: 2020-08-03, release date: 2021-08-11, Last modification date: 2024-10-23)

Primary citation

Etse, K.S.,Dorosz, J.,McLain Christensen, K.,Thomas, J.Y.,Botez Pop, I.,Goffin, E.,Colson, T.,Lestage, P.,Danober, L.,Pirotte, B.,Kastrup, J.S.,Francotte, P.
Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors.
Acs Chem Neurosci, 12:2679-2692, 2021

PubMed Abstract: On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors , although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (, , ) was examined after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of . Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.

PubMed: 34242002
DOI: 10.1021/acschemneuro.1c00255

Experimental method

X-RAY DIFFRACTION (1.9 Å)