6BAA

Cryo-EM structure of the pancreatic beta-cell KATP channel bound to ATP and glibenclamide

Summary for 6BAA

• Entry DOI: 10.2210/pdb6baa/pdb
• EMDB information: 7073
• Descriptor: ATP-sensitive inward rectifier potassium channel 11, ATP-binding cassette sub-family C member 8, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: katp, sur1, kir6.2, sulfonylurea receptor, metal transport
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 8
• Total formula weight: 887921.93

Authors

Martin, G.M.,Yoshioka, C.,Shyng, S.L. (deposition date: 2017-10-12, release date: 2017-11-01, Last modification date: 2024-11-20)

Primary citation

Martin, G.M.,Kandasamy, B.,DiMaio, F.,Yoshioka, C.,Shyng, S.L.
Anti-diabetic drug binding site in a mammalian KATPchannel revealed by Cryo-EM.
Elife, 6:-, 2017

PubMed Abstract: Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic K 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 K channel complex to inhibit channel activity.

PubMed: 29035201
DOI: 10.7554/eLife.31054

Experimental method

ELECTRON MICROSCOPY (3.63 Å)