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TitleMechanism of pharmacochaperoning in a mammalian K channel revealed by cryo-EM.
Journal, issue, pagesElife, Vol. 8, Year 2019
Publish dateJul 25, 2019
AuthorsGregory M Martin / Min Woo Sung / Zhongying Yang / Laura M Innes / Balamurugan Kandasamy / Larry L David / Craig Yoshioka / Show-Ling Shyng /
PubMed AbstractATP-sensitive potassium (K) 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- ...ATP-sensitive potassium (K) 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 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 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.
External linksPubMed:31343405 / Publisher's page
KeywordsAnimals / Binding Sites / Carbamates / Cell Line / Cricetinae / Cryoelectron Microscopy / Cysteine / Glyburide / Humans / KATP Channels / Kir6.2 channel / Mammals / Models, Molecular / Mutation / Pharmaceutical Preparations / Piperidines / Potassium Channels, Inwardly Rectifying / Protein Binding / Rats / repaglinide / MEMBRANE PROTEIN / KATP / SUR1 / RPG / GBC / apo / carbamazepine / ATP
MethodsEM (single particle)
Resolution3.65 - 4.55 A
Structure data

EMDB-20528:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and repaglinide

EMDB-20530:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and glibenclamide

EMDB-20533:
Cryo-EM structure of the pancreatic beta-cell SUR1 Apo state

EMDB-20534:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to carbamazepine

EMDB-20535:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP only

PDB-6pz9:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and repaglinide

PDB-6pza:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP and glibenclamide

PDB-6pzb:
Cryo-EM structure of the pancreatic beta-cell SUR1 Apo state

PDB-6pzc:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to carbamazepine

PDB-6pzi:
Cryo-EM structure of the pancreatic beta-cell SUR1 bound to ATP only

Chemicals

ChemComp-BJX:
Repaglinide / medication*YM / Repaglinide

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-GBM:
5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide / medication*YM / Glibenclamide

Source
  • cricetus cricetus (black-bellied hamster)
  • rattus norvegicus (Norway rat)

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