Structure of a Pancreatic ATP-Sensitive Potassium Channel

• Published in: Cell Vol. 168; no. 1-2; pp. 101 - 110.e10
• Main Authors: Li, Ningning, Wu, Jing-Xiang, Ding, Dian, Cheng, Jiaxuan, Gao, Ning, Chen, Lei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2017
• Subjects: ABCC; adenosine; adenosine triphosphate; Animals; ATP Binding Cassette Transporter, Sub-Family B - chemistry; ATP Binding Cassette Transporter, Sub-Family B - metabolism; cryo-electron microscopy; Cryoelectron Microscopy; drugs; glibenclamide; Humans; Hydrolases - chemistry; Hydrolases - metabolism; KATP; KATP Channels - chemistry; KATP Channels - metabolism; Kir; lipids; Mammals - metabolism; Mesocricetus; metabolic diseases; Mice; Models, Molecular; Phosphoinositide Phospholipase C - chemistry; Phosphoinositide Phospholipase C - metabolism; PIP2; potassium channels; Potassium Channels, Inwardly Rectifying - chemistry; Potassium Channels, Inwardly Rectifying - metabolism; sulfonylurea; Sulfonylurea Receptors - chemistry; Sulfonylurea Receptors - metabolism; SUR; KATP; SUR; sulfonylurea; Kir; glibenclamide; PIP2; ABCC; K(ATP); PIP
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.12.028

ATP-sensitive potassium channels (KATP) 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-Å 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 KATP regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP2 lipid. [Display omitted] •Pancreatic KATP channel structure is determined at 5.6-Å resolution by cryo-EM•TMD0-L0 fragment mediates the interactions between Kir6.2 and SUR1•An allosteric inhibitor bound to SUR1 stabilizes Kir6.2 in a closed conformation•PIP2 uncouples Kir6.2 from glibenclamide-bound SUR1 The structure of a pancreatic ATP-sensitive potassium channel provides insights into channel assembly and regulation.