Anti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM

Gregory M. Martin, Balamurugan Kandasamy, Frank Dimaio, Craig Yoshioka, Show Ling Shyng

Research output: Research - peer-reviewArticle

Abstract

Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic KATP channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been extensively investigated, yet it remains unclear where the drug binding pocket resides. Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. Importantly, the structure shows for the first time that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide in our model led to reduced sensitivity to glibenclamide. Our structure provides novel mechanistic insights of how sulfonylureas and ATP interact with the KATP channel complex to inhibit channel activity.

LanguageEnglish (US)
Article numbere31054
JournaleLife
Volume6
DOIs
StatePublished - Oct 16 2017

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Glyburide
Adenosine Triphosphate
Binding Sites
Pharmaceutical Preparations
Lipid Bilayers
Cricetinae
Nucleotides
Mutation
Kir6.2 channel
Lipid bilayers

ASJC Scopus subject areas

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

Cite this

Anti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM. / Martin, Gregory M.; Kandasamy, Balamurugan; Dimaio, Frank; Yoshioka, Craig; Shyng, Show Ling.

In: eLife, Vol. 6, e31054, 16.10.2017.

Research output: Research - peer-reviewArticle

Martin, Gregory M. ; Kandasamy, Balamurugan ; Dimaio, Frank ; Yoshioka, Craig ; Shyng, Show Ling. / Anti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM. In: eLife. 2017 ; Vol. 6.
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