Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

Gregory M. Martin, Min Woo Sung, Zhongying Yang, Laura M. Innes, Balamurugan Kandasamy, Larry David, Craig Yoshioka, Show-Ling Shyng

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article numbere46417
JournaleLife
Volume8
DOIs
StatePublished - Jul 1 2019

    Fingerprint

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this