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

• Published in: Cell reports (Cambridge) Vol. 27; no. 6; pp. 1848 - 1857.e4
• Main Authors: Ding, Dian, Wang, Mengmeng, Wu, Jing-Xiang, Kang, Yunlu, Chen, Lei
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2019; Elsevier
• Subjects: ABC transporter; diabetes; glibenclamide; glinides; KATP channel; Kir; KNtp; repaglinide; sulfonylurea; SUR; repaglinide; sulfonylurea; SUR; glinides; Kir; KATP channel; KNtp; diabetes; glibenclamide; ABC transporter
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.050

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 (KATP). However, the mechanisms by which RPG binds to the KATP channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic KATP 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. [Display omitted] •Structure of KATP 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 KATP 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 KATP channel, revealed by a 3.3 Å cryo-EM structure and electrophysiology experiments.