Journal
CELL
Volume 168, Issue 1-2, Pages 101-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.12.028
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Funding
- Ministry of Science and Technology of China [2016YFA0502004, 2016YFA0500700, 2013CB910404]
- National Natural Science Foundation of China [31622021, 31521062, 31422016, 31470722, 31630087]
- Young Thousand Talents Program of China
- postdoctoral foundation of the Peking-Tsinghua Center for Life Sciences, Peking University
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ATP-sensitive potassium channels ( K-ATP) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of KATP, we elucidated the structure of a hetero-octameric pancreatic KATP channel in complex with a non-competitive inhibitor glibenclamide by single-particle cryoelectron microscopy to 5.6- angstrom resolution. The structure shows that four SUR1 regulatory subunits locate peripherally and dock onto the central Kir6.2 channel tetramer through the SUR1 TMD0-L0 fragment. Glibenclamide-bound SUR1 uses TMD0-L0 fragment to stabilize Kir6.2 channel in a closed conformation. In another structural population, a putative co-purified phosphatidylinositol 4,5-bisphosphate ( PIP2) molecule uncouples Kir6.2 from glibenclamide-bound SUR1. These structural observations suggest a molecular mechanism for K-ATP regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP2 lipid.
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