|Title||Mechanism of pharmacochaperoning in a mammalian K channel revealed by cryo-EM.|
|Journal, issue, pages||Elife, Vol. 8, Year 2019|
|Publish date||Jul 25, 2019|
|Authors||Gregory M Martin / Min Woo Sung / Zhongying Yang / Laura M Innes / Balamurugan Kandasamy / Larry L David / Craig Yoshioka / Show-Ling Shyng /|
|PubMed Abstract||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- ...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 links||PubMed:31343405 / Publisher's page|
|Keywords||Animals / 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|
|Methods||EM (single particle)|
|Resolution||3.65 - 4.55 A|
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