title: Structure of a Pancreatic ATP-Sensitive Potassium Channel.
abstract: 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 KATPchannel 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 KATPregulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP2lipid.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China; School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Jing-Xiang
authors.initials: JX
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Dian
authors.initials: D
authors.lastname: Ding
authors.affiliation: Ministry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Ministry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: ninggao@mail.tsinghua.edu.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China. Electronic address: chenlei2016@pku.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D020285:Cryoelectron Microscopy; D006801:Humans; D006867:Hydrolases / Q000737:chemistry / Q000378:metabolism; D054086:KATP Channels / Q000737:chemistry* / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D008958:Models, Molecular; D054801:Phosphoinositide Phospholipase C / Q000737:chemistry / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000378:metabolism; D064233:Sulfonylurea Receptors / Q000737:chemistry / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D006867:Hydrolases; D054086:KATP Channels; D054801:Phosphoinositide Phospholipase C; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
keywords: ABCC; K(ATP); Kir; PIP(2); SUR; glibenclamide; sulfonylurea