6PZA

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

6PZA の概要

• エントリーDOI: 10.2210/pdb6pza/pdb
• EMDBエントリー: 20530
• 分子名称: ATP-binding cassette sub-family C member 8, ATP-sensitive inward rectifier potassium channel 11, 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide, ... (4 entities in total)
• 機能のキーワード: katp, sur1, gbc, membrane protein
• 由来する生物種: Cricetus cricetus (Black-bellied hamster); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 221980.48

構造登録者

Shyng, S.L.,Yoshioka, C.,Martin, G.M.,Sung, M.W. (登録日: 2019-07-31, 公開日: 2019-08-14, 最終更新日: 2024-11-06)

主引用文献

Martin, G.M.,Sung, M.W.,Yang, Z.,Innes, L.M.,Kandasamy, B.,David, L.L.,Yoshioka, C.,Shyng, S.L.
Mechanism of pharmacochaperoning in a mammalian K ATP channel revealed by cryo-EM.
Elife, 8:-, 2019

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-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.

PubMed: 31343405
DOI: 10.7554/eLife.46417

実験手法

ELECTRON MICROSCOPY (3.74 Å)