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- W2018657560 endingPage "9222" @default.
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- W2018657560 abstract "ATP sensitive potassium (KATP) channels are composed of four copies of a pore-forming inward rectifying potassium channel (Kir6.1 or Kir6.2) and four copies of a sulfonylurea receptor (SUR1, SUR2A, or SUR2B) that surround the pore. SUR proteins are members of the ATP-binding cassette (ABC) superfamily of proteins. Binding of MgATP at the SUR nucleotide binding domains (NBDs) results in NBD dimerization, and hydrolysis of MgATP at the NBDs leads to channel opening. The SUR proteins also mediate interactions with KATP channel openers (KCOs) that activate the channel, with KCO binding and/or activation involving residues in the transmembrane helices and cytoplasmic loops of the SUR proteins. Because the cytoplasmic loops make extensive interactions with the NBDs, we hypothesized that the NBDs may also be involved in KCO binding. Here, we report nuclear magnetic resonance (NMR) spectroscopy studies that demonstrate a specific interaction of the KCO pinacidil with the first nucleotide binding domain (NBD1) from SUR2A, the regulatory SUR protein in cardiac KATP channels. Intrinsic tryptophan fluorescence titrations also demonstrate binding of pinacidil to SUR2A NBD1, and fluorescent nucleotide binding studies show that pinacidil binding increases the affinity of SUR2A NBD1 for ATP. In contrast, the KCO diazoxide does not interact with SUR2A NBD1 under the same conditions. NMR relaxation experiments and size exclusion chromatography indicate that SUR2A NBD1 is monomeric under the conditions used in drug binding studies. These studies identify additional binding sites for commonly used KCOs and provide a foundation for testing binding of drugs to the SUR NBDs." @default.
- W2018657560 created "2016-06-24" @default.
- W2018657560 creator A5006466935 @default.
- W2018657560 creator A5027410091 @default.
- W2018657560 creator A5061265570 @default.
- W2018657560 date "2012-11-01" @default.
- W2018657560 modified "2023-09-26" @default.
- W2018657560 title "NMR and Fluorescence Studies of Drug Binding to the First Nucleotide Binding Domain of SUR2A" @default.
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- W2018657560 doi "https://doi.org/10.1021/bi301019e" @default.
- W2018657560 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23078514" @default.
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