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

Abstract

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 trans- and cis- JB253 bind to the same SUR1 cavity as antidiabetic sulfonylurea glibenclamide (GBM). Simulations indicate that, in contrast to trans- JB253, the cis- 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.

Structural Insights into ATP-Sensitive Potassium Channel Mechanics: A Role of Intrinsically Disordered Regions

“…An extended fragment protruding from the channel shaft and docked in the SU pocket of SUR1 allows, from one side, to keep the CTD domains of Kir6.2 activated and, from the other side, to stabilize the inward open conformation of the ABC core. The presence of Kir N-ter in the interior of the ABC-core also affects the possible binding of sulfonylureas . Moreover, the C-terminal part of N-ter is known to participate in the ATP binding. , However, we still do not have any information on what happens with N-ter when it is not bound inside the SUR1 nichethat is, when the SUR1 conformation changes to outward open.…”

“…These interactions occur in more than 80% of the simulations (see Figure a,b). Of particular interest is that L0-loop directly interacts with the residues responsible for binding sulfonylureas (anti-diabetic drugs used to close the KATP channel), namely, R1245 and E1246 …”

“…Of particular interest is that L0loop directly interacts with the residues responsible for binding sulfonylureas (anti-diabetic drugs used to close the KATP channel), namely, R1245 and E1246. 43 In addition, experimental data indicate a direct involvement of the N-terminal part of L0-loop in ATP binding at the inhibitory site in Kir6.2. The CryoEM structure of Ding et al 9 shows that the side chain of K205 in SUR1 coordinates the βand γ-phosphates of ATP.…”

Enhancing the Inhomogeneous Photodynamics of Canonical Bacteriophytochrome

“…Ligand fluctuation and diffusion are known to drive diverse conformational changes in their protein hosts, as we have previously shown. 66 − 74 In the simulations described here, we determine the FE landscape for chromophore isomerization by locally enhancing the chromophore fluctuations, mainly for the D-ring pyrrole of BV. This allows us to test the hypothesis that the mechanical signal propagation in the whole BphP-BV complex can be partially triggered starting with just local BV structural changes.…”

“…Simulating these processes using unbiased MD would only give us a fragment of the whole picture as indicated by recent applications of enhanced sampling MD to photoactive proteins. 74 , 81 We plan to employ quantum calculations (e.g., QM/MM) for the photoisomerization process in further studies.…”