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The response of ATP-sensitive K+ channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATP in channel gating. Binding to NBS2 was Mg2+-independent, but Mg2+ was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinates bound nucleotides increased the EC50 for trinitrophenyl-ADP binding to NBS2, but only in the presence of Mg2+, indicating that this mutation disrupts the ligand-induced conformational change. Comparison of nucleotide-binding with ionic currents suggests a model in which each nucleotide binding event to NBS2 of SUR1 is independent and promotes KATP activation by the same amount.

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allostery, binding, diabetes, gating, human, ligand, metabolism, molecular biophysics, structural biology, Adenosine Triphosphate, Binding Sites, Enzyme Activation, HEK293 Cells, Humans, KATP Channels, Kinetics, Magnesium, Mutagenesis, Site-Directed, Potassium Channels, Inwardly Rectifying, Protein Binding, Protein Conformation, Sulfonylurea Receptors