Inhibition Mechanism of Pancreatic K_ATP Channels by Centipede Toxin

The pancreatic adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel acts as a crucial metabolic sensor, regulating insulin secretion to maintain whole-body energy homeostasis. Gain-of-function mutations in this channel lead to neonatal diabetes mellitus, a rare disorder in which certain mutants exhibit resistance to standard sulfonylurea therapy. Recent studies have identified a centipede toxin, SpTx1, as a potent inhibitor of both human pancreatic K_ATP channels and their gain-of-function mutants. This toxin stimulates insulin secretion, offering a promising therapeutic strategy for neonatal diabetes. However, the molecular mechanism by which SpTx1 inhibits the K_ATP channel has remained unclear. Here, we report the crystal structure of SpTx1 and the cryo-electron microscopy structure of the K_ATP channel in complex with SpTx1. The structure reveals that a single SpTx1 molecule binds to the extracellular surface of the Kir6.2 tetramer. Multiple interactions at the SpTx1-Kir6.2 interface underpin the high affinity and specificity of SpTx1 for human Kir6.2. We demonstrate that SpTx1 inhibits potassium currents by physically blocking the ion conduction pore. Furthermore, a structure-guided search identified another centipede toxin, Sm3a, as a novel K_ATP channel blocker. Together, these findings provide key insights into the inhibitory mechanism of centipede toxins against the human Kir6.2-containing K_ATP channel and establish a foundation for developing these toxins into potential therapeutics for K_ATP channel-related diseases.