Molecular structure of human KATP in complex with ATP and ADP

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Abstract

In many excitable cells KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K⁺ channel Kir6.2, in the presence of Mg²⁺ and nucleotides. These structures, referred to as quatrefoil and propeller forms, were determined by single-particle cryo-EM at 3.9 Å and 5.6 Å, respectively. In both forms ATP occupies the inhibitory site in Kir6.2. The nucleotide-binding domains of SUR1 are dimerized with Mg²⁺-ATP in the degenerate site and Mg²⁺-ADP in the consensus site. A lasso extension forms an interface between SUR1 and Kir6.2 adjacent to the ATP site in the propeller form, and is disrupted in the quatrefoil form. These structures support the role of SUR1 as an ADP sensor and highlight the lasso extension as a key regulatory element in ADP's ability to override ATP inhibition.

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Kenneth Pak Kin Lee

Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Jue Chen

Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, United States

For correspondence
juechen@rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2075-4283
Roderick MacKinnon

Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, United States

For correspondence
mackinn@rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7605-4679

Funding

Human Frontier Science Program

Kenneth Pak Kin Lee

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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