1. Structural Biology and Molecular Biophysics
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Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating

  1. Gregory M Martin
  2. Craig Yoshioka
  3. Emily A Rex
  4. Jonathan F Fay
  5. Qing Xie
  6. Matthew R Whorton
  7. James Z Chen  Is a corresponding author
  8. Show-Ling Shyng  Is a corresponding author
  1. Oregon Health and Science University, United States
Research Article
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Cite this article as: eLife 2017;6:e24149 doi: 10.7554/eLife.24149

Abstract

KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity.

Article and author information

Author details

  1. Gregory M Martin

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Craig Yoshioka

    Department of Biomedical Engineering, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Emily A Rex

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jonathan F Fay

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Qing Xie

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Matthew R Whorton

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. James Z Chen

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    For correspondence
    chezh@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Show-Ling Shyng

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    For correspondence
    shyngs@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8230-8820

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK066485)

  • Show-Ling Shyng

National Institute of Diabetes and Digestive and Kidney Diseases (F31DK105800)

  • Gregory M Martin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Werner Kühlbrandt, Max Planck Institute of Biophysics, Germany

Publication history

  1. Received: December 12, 2016
  2. Accepted: January 11, 2017
  3. Accepted Manuscript published: January 16, 2017 (version 1)
  4. Version of Record published: March 9, 2017 (version 2)

Copyright

© 2017, Martin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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