1. Structural Biology and Molecular Biophysics
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Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

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Cite this article as: eLife 2019;8:e46417 doi: 10.7554/eLife.46417

Abstract

ATP-sensitive potassium (KATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic β-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse KATP inhibitors are known to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of a mammalian KATP channel bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. We found all three drugs bind within a common pocket in SUR1. Further, we found the N-terminus of Kir6.2 inserted within the central cavity of the SUR1 ABC core, adjacent the drug binding pocket. The findings reveal a common mechanism by which diverse compounds stabilize the Kir6.2 N-terminus within SUR1's ABC core, allowing it to act as a firm 'handle' for the assembly of metastable mutant SUR1-Kir6.2 complexes.

Data availability

New mass spectrometry data deposited in the PRIDE database, Project accession: PXD014498

The following data sets were generated

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. Min Woo Sung

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

    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. Laura M Innes

    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. Balamurugan Kandasamy

    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. Larry L David

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

    Department of Biomedical Engineering, Oregon Health and Science University, Portland, United States
    For correspondence
    yoshiokc@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0251-7316
  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 Institutes of Health (DK57699)

  • Show-Ling Shyng

National Institutes of Health (DK066485)

  • Show-Ling Shyng

National Institutes of Health (F31 DK105800)

  • 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. Gary Yellen, Harvard Medical School, United States

Publication history

  1. Received: February 26, 2019
  2. Accepted: July 22, 2019
  3. Accepted Manuscript published: July 25, 2019 (version 1)
  4. Version of Record published: August 19, 2019 (version 2)

Copyright

© 2019, 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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