Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM
- Oregon Health and Science University, United States
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
Article and author information
Author details
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.
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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Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM
eLife 8:e46417.
https://doi.org/10.7554/eLife.46417
