Photo-Switchable Sulfonylureas Binding to ATP-Sensitive Potassium Channel Reveal the Mechanism of Light-Controlled Insulin Release.

ATP-sensitive potassium (KATP) channels are present in numerous organs, including the heart, brain, and pancreas. Physiological opening and closing of KATPs present in pancreatic β-cells, in response to changes in the ATP/ADP concentration ratio, are correlated with insulin release into the bloodstream. Sulfonylurea drugs, commonly used in type 2 diabetes mellitus treatment, bind to the octamer KATP channels composed of four pore-forming Kir6.2 and four SUR1 subunits and increase the probability of insulin release. Azobenzene-based derivatives of sulfonylureas, such as JB253 inspired by well-established antidiabetic drug glimepiride, allow for control of this process by light. The mechanism of that phenomenon was not known until now. In this paper, we use molecular docking, molecular dynamics, and metadynamics to reveal structural determinants explaining light-controlled insulin release. We show that both and JB253 bind to the same SUR1 cavity as antidiabetic sulfonylurea glibenclamide (GBM). Simulations indicate that, in contrast to JB253, the JB253 structure generated by blue light absorption promotes open structures of SUR1, in close similarity to the GBM effect. We postulate that in the open SUR1 structures, the N-terminal tail from Kir6.2 protruding into the SUR1 pocket is stabilized by flexible enough sulfonylureas. Therefore, the adjacent Kir6.2 pore is more often closed, which in turn facilitates insulin release. Thus, KATP conductance is regulated by peptide linkers between its Kir6.2 and SUR1 subunits, a phenomenon present in other biological signaling pathways. Our data explain the observed light-modulated activity of photoactive sulfonylureas and widen a way to develop new antidiabetic drugs having reduced adverse effects.