Proteomics

Dataset Information

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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

Dataset's files

Source:
Action DRS
CBDPS_Fusion_method.JPG Other
CBDPS_settings.mxf Other
Crosslinking_mass_spectrometry_updated.docx Other
Kir6pt2_SUR1.fasta Fasta
New_Supplementary_Fig_5.pptx Other
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Publications

Mechanism of pharmacochaperoning in a mammalian K<sub>ATP</sub> 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 (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 th  ...[more]

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