Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, United States.
Department of Biomedical Engineering, Oregon Health & Science University, Portland, United States.
Elife. 2019 Jul 25;8:e46417. doi: 10.7554/eLife.46417.
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.
三磷酸腺苷敏感性钾 (K) 通道由孔形成 Kir6.2 钾通道和调节 ABC 转运蛋白磺酰脲受体 1 (SUR1) 组成，调节胰腺β细胞中的胰岛素分泌以维持葡萄糖稳态。破坏通道折叠或组装的突变会阻止细胞表面表达并导致先天性高胰岛素血症。已知结构多样的 K 抑制剂可作为药理学伴侣来纠正突变通道的表达，但机制尚不清楚。在这里，我们比较了与药理学伴侣格列本脲、瑞格列奈和卡马西平结合的哺乳动物 K 通道的冷冻电镜结构。我们发现这三种药物都结合在 SUR1 中的一个共同口袋中。此外，我们发现 Kir6.2 的 N 端插入 SUR1 ABC 核心的中央腔中，紧邻药物结合口袋。这些发现揭示了不同化合物通过稳定 SUR1 的 ABC 核心内 Kir6.2 N 端的共同机制，使它能够作为组装不稳定 SUR1-Kir6.2 复合物的坚固“把手”。
