2. Academic Validation
  3. Structural identification of vasodilator binding sites on the SUR2 subunit

Structural identification of vasodilator binding sites on the SUR2 subunit

  • Nat Commun. 2022 May 13;13(1):2675. doi: 10.1038/s41467-022-30428-y.
Dian Ding 1 2 3 4,  Jing-Xiang Wu 1 4,  Xinli Duan 5,  Songling Ma 5,  Lipeng Lai 5,  Lei Chen 6 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, 100871, Beijing, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China.
  • 3 Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China.
  • 4 National Biomedical Imaging Center, Peking University, 100871, Beijing, China.
  • 5 Beijing Jingtai Technology Co., Ltd., Beijing, China.
  • 6 State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, 100871, Beijing, China. [email protected].
  • 7 Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China. [email protected].
  • 8 Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China. [email protected].
  • 9 National Biomedical Imaging Center, Peking University, 100871, Beijing, China. [email protected].
PMID: 35562524 DOI: 10.1038/s41467-022-30428-y
Abstract

ATP-sensitive potassium channels (KATP), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing KATP channels by class of small molecule drugs known as KATP openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, KATP openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to KATP and how they activate the channel remains elusive. Here, we present cryo-EM structures of SUR2A and SUR2B subunits in complex with Mg-nucleotides and P1075 or levcromakalim, two chemically distinct KATP openers that are specific to SUR2. Both P1075 and levcromakalim bind to a common site in the transmembrane domain (TMD) of the SUR2 subunit, which is between TMD1 and TMD2 and is embraced by TM10, TM11, TM12, TM14, and TM17. These KATP openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel.

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