The Structural Basis for the Binding of Repaglinide to the Pancreatic K ATP 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 ). However, the mechanisms by which RPG binds to the K channel are poorly understood. Here, we...

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Published inCell reports (Cambridge) Vol. 27; no. 6; p. 1848
Main Authors Ding, Dian, Wang, Mengmeng, Wu, Jing-Xiang, Kang, Yunlu, Chen, Lei
Format Journal Article
LanguageEnglish
Published United States 07.05.2019
Subjects
repaglinide
SUR
sulfonylurea
Kir
glinides
KNtp
ABC transporter
diabetes
glibenclamide
K(ATP) channel
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Summary: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 ). However, the mechanisms by which RPG binds to the K channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic K 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.
ISSN:2211-1247
DOI:10.1016/j.celrep.2019.04.050