9DFX

Cryo-EM structure of a SUR1/Kir6.2 ATP-sensitive potassium channel in the presence of Aekatperone in the closed conformation

This is a non-PDB format compatible entry.

Summary for 9DFX

• Entry DOI: 10.2210/pdb9dfx/pdb
• EMDB information: 46820
• Descriptor: ATP-sensitive inward rectifier potassium channel 11, SUR1, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: atp-sensitive potassium channel, katp channel, sur1, kir6.2, potassium transport, metabolic sensor, congenital hyperinsulinism, trafficking, pharmacochaperone, transport protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 5
• Total formula weight: 355334.84

Authors

Driggers, C.M.,ElSheikh, A.,Shyng, S.-L. (deposition date: 2024-08-30, release date: 2025-02-12, Last modification date: 2025-04-09)

Primary citation

Elsheikh, A.,Driggers, C.M.,Truong, H.H.,Yang, Z.,Allen, J.,Henriksen, N.M.,Walczewska-Szewc, K.,Shyng, S.L.
AI-based discovery and cryoEM structural elucidation of a K ATP channel pharmacochaperone.
Elife, 13:-, 2025

PubMed Abstract: Pancreatic K channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the K channel opener diazoxide, the mainstay medical therapy for CHI. Current clinically used K channel inhibitors have been shown to act as pharmacochaperones and restore surface expression of trafficking mutants; however, their therapeutic utility for K trafficking-impaired CHI is hindered by high affinity binding, which limits functional recovery of rescued channels. Recent structural studies of K channels employing cryo-electron microscopy (cryoEM) have revealed a promiscuous pocket where several known K pharmacochaperones bind. The structural knowledge provides a framework for discovering K channel pharmacochaperones with desired reversible inhibitory effects to permit functional recovery of rescued channels. Using an AI-based virtual screening technology AtomNet followed by functional validation, we identified a novel compound, termed Aekatperone, which exhibits chaperoning effects on K channel trafficking mutations. Aekatperone reversibly inhibits K channel activity with a half-maximal inhibitory concentration (IC) ~9 μM. Mutant channels rescued to the cell surface by Aekatperone showed functional recovery upon washout of the compound. CryoEM structure of K bound to Aekatperone revealed distinct binding features compared to known high affinity inhibitor pharmacochaperones. Our findings unveil a K pharmacochaperone enabling functional recovery of rescued channels as a promising therapeutic for CHI caused by K trafficking defects.

PubMed: 40135739
DOI: 10.7554/eLife.103159

Experimental method

ELECTRON MICROSCOPY (4.1 Å)