The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel

Repaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium channel (K-ATP). However, the mechanisms by which RPG binds to the K-ATP channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic K-ATP channel in complex with inhibitory RPG and adenosine-5'-(gamma-thio)-triphosphate (ATP gamma S) at 3.3 angstrom and a medium-resolution structure of a RPG-bound mini SUR1 protein in which the N terminus of the inward-rectifying potassium channel 6.1 (Kir6.1) is fused to the ABC transporter module of the sulfonylurea receptor 1 (SUR1). These structures reveal the binding site of RPG in the SUR1 subunit. Furthermore, the high-resolution structure reveals the complex architecture of the ATP binding site, which is formed by both Kir6.2 and SUR1 subunits, and the domain-domain interaction interfaces.