Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28092267.
- Also identified by DOI 10.7554/eLife.24149 and PMC identifier 5344670.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
K<sub>ATP</sub> 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 PIP<sub>2</sub> binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP<sub>2</sub> 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.
Medical subject headings
- Cryoelectron Microscopy
- Potassium Channels, Inwardly Rectifying
- Sulfonylurea Receptors