Abstract
Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic KATP channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been extensively investigated, yet it remains unclear where the drug binding pocket resides. Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. Importantly, the structure shows for the first time that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide in our model led to reduced sensitivity to glibenclamide. Our structure provides novel mechanistic insights of how sulfonylureas and ATP interact with the KATP channel complex to inhibit channel activity.
Highlights
ATP-sensitive potassium (KATP) channels are unique hetero-octameric complexes each composed of four inwardly rectifying Kir6 channel subunits and four sulfonylurea receptor (SUR) subunits belonging to the ATP binding cassette (ABC) transporter protein family (Aguilar-Bryan and Bryan, 1999; Nichols, 2006)
Each Kir6.2 has the typical Kir channel architecture of an N-terminal cytoplasmic domain, a transmembrane domain (TMD) consisting of two TMs termed M1 and M2 interspersed by a pore loop and selectivity filter, and a “tether” helix that links the TMD to the larger C-terminal cytoplasmic domain (CTD) (Fig.2A, Fig.2-figure supplement 1)
SUR1 is found in an “inward-facing” conformation, with nucleotide binding domains (NBDs) clearly separated and the vestibule formed by TMD1/TMD2 open towards the cytoplasm
Summary
ATP-sensitive potassium (KATP) channels are unique hetero-octameric complexes each composed of four inwardly rectifying Kir channel subunits and four sulfonylurea receptor (SUR) subunits belonging to the ATP binding cassette (ABC) transporter protein family (Aguilar-Bryan and Bryan, 1999; Nichols, 2006). In pancreatic β-cells, KATP channels formed by Kir6.2 and SUR1 are gated by intracellular ATP and ADP, with ATP inhibiting channel activity while Mg2+complexed ATP and ADP stimulating channel activity (Aguilar-Bryan and Bryan, 1999; Ashcroft, 2007). The intracellular ATP to ADP ratio increases following glucose metabolism, which favors channel closure by ATP, resulting in membrane depolarization, Ca2+ influx, and exocytosis of insulin granules. In this way, KATP channels are able to control insulin secretion according to blood glucose levels. The pivotal role of KATP channels in insulin secretion regulation makes them an important drug target
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