What question did this study set out to answer?

To elucidate the structural basis of inhibition of vascular KATP channels by VU0542270.

February 21, 2026

BPS2026 - Structural basis of vascular-specific KATP channel inhibition by VU0542270

SLSun‐Joo LeeWashington University in St. Louis CDCamden DriggersOregon Health & Science University YKYi-Ying M. KuoOregon Health & Science University

Key Points

To elucidate the structural basis of inhibition of vascular KATP channels by VU0542270.
Employing high-throughput screening to identify VU0542270
Using single particle cryo-EM to determine channel structure
Conducting molecular dynamics simulations of channel interactions
Performing mutagenesis to identify critical residues for binding
VU0542270 specifically inhibits vascular KATP channels over SUR1-dependent channels
Cryo-EM map showed binding pocket overlaps with known sulfonylurea sites
Residue Tyr1209 in SUR2 crucial for greater inhibition effects

Abstract

In the human body, K ATP channels control cell excitability in response to the cellular metabolic state, with three major isoforms generated by different combinations of the pore-forming (Kir6.x) and auxiliary sulfonylurea receptor (SURx) subunits: pancreatic K ATP channels are composed of Kir6.2 and SUR1; skeletal and cardiac muscle K ATP channels are composed of Kir6.2 and SUR2A; and vascular K ATP channels are composed of Kir6.1 and SUR2B. Loss- or gain-of-function (LOF or GOF) mutations in these K ATP channel subunits can lead to multisymptomatic conditions such as congenital hyperinsulinism, neonatal diabetes mellitus, Cantu syndrome, and ABCC9-related Intellectual disability myopathy syndrome (AIMS).Despite decades of effort, isoform-specific inhibitors for vascular-type K ATP channels have yet to be developed. A recent high-throughput screening study discovered a small molecule K ATP inhibitor (VU0542270) with relative specificity for SUR2- over SUR1-dependent channels, which could lead to therapeutic agents to treat SUR2-dependent GOF (Cantu Syndrome) or the congenital heart defect patent ductus arteriosus (PDA), with minimal adverse side effects on SUR1 and blood sugar control. To elucidate the structural and molecular mechanisms of such specificity we have employed single particle cryo-EM, molecular dynamics, and functional characterization of the changes in drug effect on mutant channels guided by the determined structures. Our cryo-EM map determined at 3.5 Å resolution in the presence of VU0542270 indicated that the vascular K ATP -specific drug also binds at the same pocket previously identified for sulfonylureas and other SUR-acting inhibitors. Subsequent mutagenesis showed that Tyr at residue 1209 in SUR2 is necessary for the relatively greater VU0542270 inhibition of SUR2- versus SUR1-dependent channels. Identification of the VU0542270 interaction site paves the way for rational drug design to further optimize binding to enhance potency and specificity.

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