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Elife. 2017 Jan 16;6. pii: e24149. doi: 10.7554/eLife.24149.

Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating.

Author information

1
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, United States.
2
Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States.
3
Vollum Institute, Oregon Health and Science University, Portland, Oregon, United States.

Abstract

KATP channels 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 PIP2 binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2 binding 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.

KEYWORDS:

ABC transporter; ATP; biophysics; inward rectifier; none; structural biology; sulfonylurea; sulfonylurea receptor

PMID:
28092267
PMCID:
PMC5344670
DOI:
10.7554/eLife.24149
[Indexed for MEDLINE]
Free PMC Article

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