5OEW

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with glutamate and positive allosteric modulator BPAM538

Summary for 5OEW

• Entry DOI: 10.2210/pdb5oew/pdb
• Descriptor: Glutamate receptor 2, GLUTAMIC ACID, ZINC ION, ... (6 entities in total)
• Functional Keywords: ionotropic glutamate receptor glua2. ligand-binding domain, positive allosteric modulator, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P19491
• Total number of polymer chains: 3
• Total formula weight: 90318.51

Authors

Larsen, A.P.,Frydenvang, K.A.,Kastrup, J.S. (deposition date: 2017-07-10, release date: 2018-01-03, Last modification date: 2024-11-13)

Primary citation

Goffin, E.,Drapier, T.,Larsen, A.P.,Geubelle, P.,Ptak, C.P.,Laulumaa, S.,Rovinskaja, K.,Gilissen, J.,Tullio, P.,Olsen, L.,Frydenvang, K.,Pirotte, B.,Hanson, J.,Oswald, R.E.,Kastrup, J.S.,Francotte, P.
7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency.
J. Med. Chem., 61:251-264, 2018

PubMed Abstract: We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, EC = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range.

PubMed: 29256599
DOI: 10.1021/acs.jmedchem.7b01323

Experimental method

X-RAY DIFFRACTION (2 Å)