Back to Search
Start Over
The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel
- Source :
- Cell Reports, Vol 27, Iss 6, Pp 1848-1857.e4 (2019)
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- 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 (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. : 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. Keywords: diabetes, KATP channel, repaglinide, glibenclamide, sulfonylurea, glinides, Kir, SUR, ABC transporter, KNtp
- Subjects :
- 0301 basic medicine
endocrine system
Chemistry
Protein subunit
Insulin
medicine.medical_treatment
ATP-binding cassette transporter
Repaglinide
General Biochemistry, Genetics and Molecular Biology
Potassium channel
Cell biology
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
lcsh:Biology (General)
medicine
Sulfonylurea receptor
Secretagogue
Binding site
lcsh:QH301-705.5
030217 neurology & neurosurgery
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 27
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....c47addb5fee55a96795a10635027dcb9