Structural identification of vasodilator binding sites on the SUR2 subunit.

ATP-sensitive potassium channels (K(ATP)), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing K(ATP) channels by class of small molecule drugs known as K(ATP) openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, K(ATP) openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to K(ATP) 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(ATP) 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(ATP) openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel.