Structural identification of vasodilator binding sites on the SUR2 subunit.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35562524.
- Also identified by DOI 10.1038/s41467-022-30428-y and PMC identifier 9106677.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
ATP-sensitive potassium channels (K<sub>ATP</sub>), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing K<sub>ATP</sub> channels by class of small molecule drugs known as K<sub>ATP</sub> openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, K<sub>ATP</sub> openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to K<sub>ATP</sub> 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 K<sub>ATP</sub> 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 K<sub>ATP</sub> openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel.
Medical subject headings
- Potassium Channels, Inwardly Rectifying
- Vasodilator Agents