Mechanism of pharmacochaperoning in a mammalian K<sub>ATP</sub> channel revealed by cryo-EM.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31343405.
- Also identified by DOI 10.7554/eLife.46417 and PMC identifier 6699824.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
ATP-sensitive potassium (K<sub>ATP</sub>) 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 K<sub>ATP</sub> 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 K<sub>ATP</sub> 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.
Medical subject headings
- Cryoelectron Microscopy
- KATP Channels
- Mammals
- Pharmaceutical Preparations