NMR Approaches to Functional Dynamics of Genetically Separated iGluR Domains

Ptak, Christopher; Ahmed, Ahmed H.; Oswald, Robert E.

doi:10.1007/978-1-4939-2812-5_8

Cited by 1 publication

(3 citation statements)

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“…44 The structures were refined using individual isotropic B values, TLS, NCS and riding H-atoms. The structures were validated by build-in tools in COOT , MolProbity 45 in PHENIX and the wwPDB Validation Service. Domain closure of GluA2-LBD relative to the apo structure of GluA2-LBD (PDB entry 1FTO, mol A ) was calculated using the DynDom server.…”

Section: Methodsmentioning

confidence: 99%

“…GluA2-LBD-N775S was uniformly labeled with 15 N and prepared for NMR spectroscopy as described previously. 47 Spectra were collected on a Bruker AVANCE III HD 800 MHz NMR spectrometer at the SUNY ESF NMR facility. A total of 1024 complex points were collected in the proton dimension (spectral width of 14423 Hz), and 128 complex increments were collected in the nitrogen dimension (spectral width of 3080 Hz).…”

Section: Accession Codesmentioning

confidence: 99%

“…GluA2-LBD-N775S was uniformly labeled with 15 N and prepared for NMR spectroscopy as described previously . Spectra were collected on a Bruker AVANCE III HD 800 MHz NMR spectrometer at the SUNY ESF NMR facility.…”

Section: Experimental Sectionmentioning

confidence: 99%

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7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency

et al. 2017

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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, EC50=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) is 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.

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Section: Methodsmentioning

confidence: 99%

Section: Accession Codesmentioning

confidence: 99%