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

Author:

Martin Gregory M1,Yoshioka Craig2,Rex Emily A1,Fay Jonathan F1,Xie Qing1,Whorton Matthew R3,Chen James Z1,Shyng Show-Ling1ORCID

Affiliation:

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.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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