Abstract
KATP channels consist of four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodilation of arterial smooth muscle cells. Abnormal channel function resulting from inherited gain or loss-of-function mutations in either the Kir6.x and/or SUR subunits are associated with severe diseases such as neonatal diabetes, congenital hyperinsulinism, or Cantú syndrome (CS). CS is an ultra-rare genetic autosomal dominant disorder, caused by dominant gain-of-function mutations in SUR2A or Kir6.1 subunits. No specific pharmacotherapeutic treatment options are currently available for CS. Kir6 specific inhibitors could be beneficial for the development of novel drug therapies for CS, particular for mutations, which lack high affinity for sulfonylurea inhibitor glibenclamide. By applying a combination of computational methods including atomistic MD simulations, free energy calculations and pharmacophore modeling, we identified several novel Kir6.1 inhibitors, which might be possible candidates for drug repurposing. The in silico predictions were confirmed using inside/out patch-clamp analysis. Importantly, Cantú mutation C166S in Kir6.2 (equivalent to C176S in Kir6.1) and S1020P in SUR2A, retained high affinity toward the novel inhibitors. Summarizing, the inhibitors identified in this study might provide a starting point toward developing novel therapies for Cantú disease.
Highlights
Cantú syndrome (CS) is a rare genetic autosomal dominant disorder caused by dominant gain-of-function mutations in the ATP-dependent potassium (KATP) channel genes ABCC9 (Harakalova et al, 2012; Van Bon et al, 2012) and KCNJ8 (Brownstein et al, 2013; Cooper et al, 2014, 2017), encoding sulfonylurea receptor 2 SUR2 and inward rectifier potassium channel 6.1 Kir6.1, respectively
Based on the experimental finding that RSG predominantly acts on the long-closed state of Kir6.1 channels (Yu et al, 2012), a homology model of the Kir6.1 pore model was constructed using the closed state crystal structure of the Kir3.2 channel [Protein Data Bank (PDB) code: 3SYA (Whorton and MacKinnon, 2011)] as template
The root mean square deviation (RMSD) of the Kir6.1 model converged to ∼4 Å at around 100 ns, indicating that the simulated systems are stable and at equilibrium
Summary
Cantú syndrome (CS) is a rare genetic autosomal dominant disorder caused by dominant gain-of-function mutations in the ATP-dependent potassium (KATP) channel genes ABCC9 (Harakalova et al, 2012; Van Bon et al, 2012) and KCNJ8 (Brownstein et al, 2013; Cooper et al, 2014, 2017), encoding sulfonylurea receptor 2 SUR2 and inward rectifier potassium channel 6.1 Kir6.1, respectively. Starting from January 2017, the first (near-)atomic resolution structures (resolution ranges from 3.63 to 6.3 Å) of these hetero-octameric complexes have been solved by cryo-EM microscopy by three independent labs (Lee et al, 2017; Li et al, 2017; Martin et al, 2017a,b; Wu et al, 2018). These structures confirm that KATP channels are formed by four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits
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