Mechanism of pharmacochaperoning in ATP-sensitive potassium channels 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 beta-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 have been shown to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of K-ATP channels bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. DSP cross-linking mass spectrometry was used to partially confirm cryoEM structures.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Type B Pancreatic Cell, Cell Culture

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Phillip Wilmarth  

LAB HEAD: Show-Ling Shyng

PROVIDER: PXD013873 | Pride | 2019-11-12

REPOSITORIES: Pride