Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides

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

doi:10.1038/s41467-022-30430-4

Structural insights into the mechanism of pancreatic K_ATP channel regulation by nucleotides

Nat Commun. 2022 May 19;13(1):2770. doi: 10.1038/s41467-022-30430-4.

Authors

Mengmeng Wang^{1

2

3

4}, Jing-Xiang Wu^{1

4}, Dian Ding^{1

2

3

4}, Lei Chen^{5

6

7

8}

Affiliations

¹ State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, 100871, Beijing, China.
² Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China.
³ Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China.
⁴ National Biomedical Imaging Center, Peking University, 100871, Beijing, China.
⁵ State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, 100871, Beijing, China. chenlei2016@pku.edu.cn.
⁶ Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China. chenlei2016@pku.edu.cn.
⁷ Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China. chenlei2016@pku.edu.cn.
⁸ National Biomedical Imaging Center, Peking University, 100871, Beijing, China. chenlei2016@pku.edu.cn.

Abstract

ATP-sensitive potassium channels (K_ATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic K_ATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of K_ATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type K_ATP openers.

Publication types

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

MeSH terms

Adenosine Diphosphate / metabolism
Adenosine Triphosphate* / metabolism
Humans
KATP Channels* / metabolism
Pancreas / metabolism
Sulfonylurea Receptors / metabolism

Substances

KATP Channels
Sulfonylurea Receptors
Adenosine Diphosphate
Adenosine Triphosphate