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 Whorton, James Z. Chen, Show-Ling Shyng

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

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

Fingerprint

KATP Channels
Glyburide
Adenosine Triphosphate
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; Chen, James Z.; Shyng, Show-Ling.

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

Research output: Contribution to journalArticle

@article{210bdfedf6da4bd5975b9ed717faed64,
title = "Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating",
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 {\AA} 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.",
author = "Martin, {Gregory M.} and Craig Yoshioka and Rex, {Emily A.} and Fay, {Jonathan F.} and Qing Xie and Matthew Whorton and Chen, {James Z.} and Show-Ling Shyng",
year = "2017",
month = "1",
day = "16",
doi = "10.7554/eLife.24149",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating

AU - Martin, Gregory M.

AU - Yoshioka, Craig

AU - Rex, Emily A.

AU - Fay, Jonathan F.

AU - Xie, Qing

AU - Whorton, Matthew

AU - Chen, James Z.

AU - Shyng, Show-Ling

PY - 2017/1/16

Y1 - 2017/1/16

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85014959849&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014959849&partnerID=8YFLogxK

U2 - 10.7554/eLife.24149

DO - 10.7554/eLife.24149

M3 - Article

C2 - 28092267

AN - SCOPUS:85014959849

VL - 6

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e24149

ER -