6PZC

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

Summary for 6PZC

• Entry DOI: 10.2210/pdb6pzc/pdb
• EMDB information: 20528 20530 20533 20534 20535
• Descriptor: ATP-binding cassette sub-family C member 8 (1 entity in total)
• Functional Keywords: katp, sur1, carbamazepine, membrane protein
• Biological source: Cricetus cricetus (Black-bellied hamster)
• Total number of polymer chains: 1
• Total formula weight: 177333.58

Authors

Shyng, S.L.,Yoshioka, C.,Martin, G.M.,Sung, M.W. (deposition date: 2019-07-31, release date: 2019-08-14, Last modification date: 2024-03-20)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (4.34 Å)