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

Gregory M. Martin, Craig Yoshioka, Emily A. Rex, Jonathan F. Fay, Qing Xie, Matthew R. Whorton, James Z. Chen, Show Ling Shyng

Research output: Research - peer-reviewArticle

  • 14 Citations

Abstract

KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic b-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 inwardfacing 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.

LanguageEnglish (US)
Article numbere24149
JournaleLife
Volume6
DOIs
StatePublished - Jan 16 2017

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KATP Channels
Adenosine Triphosphate
Glyburide
Hypoglycemic Agents
Conformations
Nucleotides
Binding Sites
Insulin
Membranes
Sensors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. / Martin, Gregory M.; Yoshioka, Craig; Rex, Emily A.; Fay, Jonathan F.; Xie, Qing; Whorton, Matthew R.; Chen, James Z.; Shyng, Show Ling.

In: eLife, Vol. 6, e24149, 16.01.2017.

Research output: Research - peer-reviewArticle

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AU - Xie,Qing

AU - Whorton,Matthew R.

AU - Chen,James Z.

AU - Shyng,Show Ling

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AB - KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic b-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 inwardfacing 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.

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