PT  - JOURNAL ARTICLE
AU  - Gregory M. Martin
AU  - Balamurugan Kandasamy
AU  - Frank DiMaio
AU  - Craig Yoshioka
AU  - Show-Ling Shyng
TI  - Anti-diabetic drug binding site in K<sub>ATP</sub> channels revealed by Cryo-EM
AID  - 10.1101/172908
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 172908
4099  - http://biorxiv.org/content/early/2017/08/05/172908.1.short
4100  - http://biorxiv.org/content/early/2017/08/05/172908.1.full
AB  - 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 the channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.8Å resolution, which reveals in 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.