TY - JOUR TI - Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM AU - Martin, Gregory M AU - Sung, Min Woo AU - Yang, Zhongying AU - Innes, Laura M AU - Kandasamy, Balamurugan AU - David, Larry L AU - Yoshioka, Craig AU - Shyng, Show-Ling A2 - Aldrich, Richard A2 - Yellen, Gary A2 - Moiseenkova-Bell, Vera Y A2 - Nichols, Colin G A2 - Agar, Jeffrey VL - 8 PY - 2019 DA - 2019/07/25 SP - e46417 C1 - eLife 2019;8:e46417 DO - 10.7554/eLife.46417 UR - https://doi.org/10.7554/eLife.46417 AB - ATP-sensitive potassium (KATP) 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 KATP 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 KATP 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. KW - ABC transporter KW - glibenclamide KW - repaglinide KW - carbamazepine KW - sulfonylurea receptor KW - inward rectifier potassium channel JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -