Dataset Information

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. CyanurBiotinDimercaptoPropionylSuccinimide (CBDPS) 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: PXD014498 | Pride | 2019-08-12

REPOSITORIES: Pride

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Publications

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

Martin Gregory M GM Sung Min Woo MW Yang Zhongying Z Innes Laura M LM Kandasamy Balamurugan B David Larry L LL Yoshioka Craig C Shyng Show-Ling SL

eLife 20190725

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 th ...[more]

PMID: 31343405

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Dataset Information

Mechanism of pharmacochaperoning in ATP-sensitive potassium channels revealed by cryo-EM

Publications

Mechanism of pharmacochaperoning in a mammalian K<sub>ATP</sub> channel revealed by cryo-EM.

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