Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels

Jing-Xiang Wu,Mengmeng Wang,Dian Ding,Lei Chen,Yunlu Kang,Xin Zeng

doi:10.1007/s13238-018-0530-y

Jing-Xiang Wu, Mengmeng Wang + Show 4 more

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https://doi.org/10.1007/s13238-018-0530-y

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Journal: Protein & cell	Publication Date: Mar 28, 2018
Citations: 99	License type: open-access

Affiliation: Peking University, Center for Life Sciences

Abstract

ATP-sensitive potassium channels (KATP) are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic KATP channels control insulin release and regulate metabolism at the whole body level. They are implicated in many metabolic disorders and diseases and are therefore important drug targets. Here, we present three structures of pancreatic KATP channels solved by cryo-electron microscopy (cryo-EM), at resolutions ranging from 4.1 to 4.5 Å. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 (inward-rectifying potassium channel 6.2) N-terminus participates in the coupling between the peripheral SUR1 (sulfonylurea receptor 1) subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit.

Highlights

ATP-sensitive potassium channels (KATP) are ion channels that selectively allow potassium ions to permeate the cell.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Their channel activities are tightly regulated by endogenous nucleotide metabolites
These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how inward-rectifying potassium channel 6 (Kir6).2 N-terminus participates in the coupling between the peripheral SUR1 subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit
Fusion construct with a 6 amino acids (6AA) linker was previously used to elucidate the association and stoichiometry of KATP channels (Clement et al, 1997) and was recently used to solve the structure of KATP channel in complex with Mg-ATP and Mg-ADP (Lee et al, 2017)

Summary

Introduction

Their channel activities are tightly regulated by endogenous nucleotide metabolites. They are inhibited by ATP and activated by Mg-ADP. By sensing the intracellular ADP/ATP ratio, KATP channels tune the potassium ion efflux across the plasma membrane and adjust the membrane potential. Relevant sulfonylureas drugs inhibit pancreatic KATP channels and serve as insulin secretagogues for the treatment of type II diabetes (Bryan et al, 2005), while KATP activators, such as potassium channel openers (KCOs), are used for hypoglycemia and show promise for myoprotection (Flagg et al, 2010; Hibino et al, 2010)

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