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

ABSTRACT: ATP-sensitive potassium (K_ATP) 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_ATP 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_ATP 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 ce

SUBMITTER: Martin GM 

PROVIDER: S-EPMC6699824 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature