title: Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating.
abstract: KATPchannels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6 Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Martin
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Yoshioka
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Rex
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Fay
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Whorton
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: James Z
authors.initials: JZ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Show-Ling
authors.identifier: 0000-0002-8230-8820
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020285:Cryoelectron Microscopy; D005905:Glyburide / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism* / Q000648:ultrastructure*; D011487:Protein Conformation; D055503:Protein Multimerization; D064233:Sulfonylurea Receptors / Q000378:metabolism* / Q000648:ultrastructure*; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D005905:Glyburide; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat
keywords: ABC transporter; ATP; biophysics; inward rectifier; none; structural biology; sulfonylurea; sulfonylurea receptor