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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'-(γ-thio)-triphosphate (ATPγS) at 3.3 Å 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. • Structure of K ATP channel bound to repaglinide is determined at 3.3 Å resolution • Repaglinide binds in the central vestibule of the SUR1 subunit to inhibit NBD closure • Repaglinide recruits the Kir6 N terminus to inhibit K ATP channel gating • High-resolution map shows that SUR1 K205 is involved in inhibitory ATP coordination Ding et al. report the detailed binding site and the inhibitory mechanism of the insulin secretagogue repaglinide on the pancreatic K ATP channel, revealed by a 3.3 Å cryo-EM structure and electrophysiology experiments. [ABSTRACT FROM AUTHOR]

Summary ATP-sensitive potassium channels (K ATP ) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of K ATP , we elucidated the structure of a hetero-octameric pancreatic K ATP channel in complex with a non-competitive inhibitor glibenclamide by single-particle cryoelectron microscopy to 5.6-Å resolution. The structure shows that four SUR1 regulatory subunits locate peripherally and dock onto the central Kir6.2 channel tetramer through the SUR1 TMD0-L0 fragment. Glibenclamide-bound SUR1 uses TMD0-L0 fragment to stabilize Kir6.2 channel in a closed conformation. In another structural population, a putative co-purified phosphatidylinositol 4,5-bisphosphate (PIP 2 ) molecule uncouples Kir6.2 from glibenclamide-bound SUR1. These structural observations suggest a molecular mechanism for K ATP regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP 2 lipid. [ABSTRACT FROM AUTHOR]