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TitleAI-based discovery and cryoEM structural elucidation of a K channel pharmacochaperone.
Journal, issue, pagesElife, Vol. 13, Year 2025
Publish dateMar 26, 2025
AuthorsAssmaa Elsheikh / Camden M Driggers / Ha H Truong / Zhongying Yang / John Allen / Niel M Henriksen / Katarzyna Walczewska-Szewc / Show-Ling Shyng /
PubMed AbstractPancreatic 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 ...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.
External linksElife / PubMed:40135739 / PubMed Central
MethodsEM (single particle)
Resolution4.1 Å
Structure data

46820

9dfx

EMDB-46820, PDB-9dfx:
Cryo-EM structure of a SUR1/Kir6.2 ATP-sensitive potassium channel in the presence of Aekatperone in the closed conformation
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-K:
Unknown entry

PDB-1a4f:
BAR-HEADED GOOSE HEMOGLOBIN (OXY FORM)

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • rattus norvegicus (Norway rat)
  • mesocricetus auratus (golden hamster)
KeywordsTRANSPORT PROTEIN / ATP-sensitive potassium channel / KATP channel / SUR1 / Kir6.2 / potassium transport / metabolic sensor / congenital hyperinsulinism / trafficking / pharmacochaperone

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