5O9A
Crystal structure of the GluA2 ligand-binding domain (S1S2J-L504Y-N775S) in complex with glutamate and BPAM121 at 1.78 A resolution
Summary for 5O9A
| Entry DOI | 10.2210/pdb5o9a/pdb |
| Descriptor | Glutamate receptor 2,Glutamate receptor 2, SULFATE ION, 7-chloro-4-(2-fluoroethyl)-2,3-dihydro-1,2,4-benzothiadiazine 1,1-dioxide, ... (10 entities in total) |
| Functional Keywords | ampa receptor, ligand-binding domain, positive allosteric modulator, membrane protein, signaling protein, ionotropic glutamate receptor, glua2, glur2, l504y-n775s |
| Biological source | Rattus norvegicus (Norway Rat) More |
| Cellular location | Cell membrane ; Multi-pass membrane protein : P19491 |
| Total number of polymer chains | 4 |
| Total formula weight | 121368.12 |
| Authors | Laulumaa, S.,Rovinskaja, K.,Frydenvang, K.A.,Kastrup, J.S. (deposition date: 2017-06-16, release date: 2018-01-03, Last modification date: 2024-10-16) |
| 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 Cited by 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: 29256599DOI: 10.1021/acs.jmedchem.7b01323 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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