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

Dian Ding; Mengmeng Wang; Jing-Xiang Wu; Yunlu Kang; Lei Chen

doi:10.1016/j.celrep.2019.04.050

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

Cell Rep. 2019 May 7;27(6):1848-1857.e4. doi: 10.1016/j.celrep.2019.04.050.

Authors

Dian Ding¹, Mengmeng Wang¹, Jing-Xiang Wu², Yunlu Kang³, Lei Chen⁴

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
² State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
³ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China.
⁴ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: chenlei2016@pku.edu.cn.

PMID: 31067468
DOI: 10.1016/j.celrep.2019.04.050

Abstract

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.

Keywords: ABC transporter; K(ATP) channel; KNtp; Kir; SUR; diabetes; glibenclamide; glinides; repaglinide; sulfonylurea.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / analogs & derivatives
Adenosine Triphosphate / chemistry
Adenosine Triphosphate / metabolism
Amino Acid Motifs
Amino Acid Sequence
Animals
Binding Sites
Carbamates / chemistry*
Carbamates / metabolism*
HEK293 Cells
Humans
Mice
Models, Molecular
Pancreas / metabolism*
Piperidines / chemistry*
Piperidines / metabolism*
Potassium Channels, Inwardly Rectifying / chemistry*
Potassium Channels, Inwardly Rectifying / metabolism*
Protein Binding
Protein Interaction Mapping
Protein Subunits / chemistry
Protein Subunits / metabolism
Sulfonylurea Receptors / chemistry
Sulfonylurea Receptors / metabolism
Sulfonylurea Receptors / ultrastructure

Substances

Carbamates
Piperidines
Potassium Channels, Inwardly Rectifying
Protein Subunits
Sulfonylurea Receptors
adenosine 5'-O-(3-thiotriphosphate)
repaglinide
Adenosine Triphosphate