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Peer-reviewedCC BYScience Advances

Structural and kinetic mechanisms of state-dependent potassium channel inhibition

  • Efthimios Kyriakis1
  • Agnese Roscioni2,3
  • Jodene Eldstrom1
  • Daniel Sastre1
  • Ying Dou1
  • Alice Taddei2
  • Steven Molinarolo4
  • Michael Tian1
  • Luca Maragliano2,3
  • Filip Van Petegem4
  • David Fedida1
4 affiliations
  1. 1The Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver V6T 1Z3, Canada.
  2. 2Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona 60131, Italy.
  3. 3Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy.
  4. 4The Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver V6T 1Z3, Canada.
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Abstract

) channel plays a critical role in cardiac repolarization, while loss- or gain-of-function mutations increase the risk of life-threatening arrythmias and sudden death. Like many channels, KCNQ1 exhibits state-dependent pharmacological properties with inhibitors such as UCL2077 displaying higher potency for intermediate over activated states. Here, we report cryo-EM structures and MD simulations of KCNQ1 in complex with UCL2077 in two activation states. UCL2077 breaks tetrameric symmetry and binds in diagonally opposed protomers in pockets formed by the S5-S6 helices from one protomer and the S6 of an adjacent protomer. UCL2077 binding drives distortion of the S6 helix and causes an allosteric collapse of the pore. Specificity arises via structural configurations in the pore that occur with greater frequency in the intermediate state and are stabilized upon drug binding.

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Cite

BibTeXRIS
BibTeX
@article{kyriakis2026structural,
  title = {{Structural and kinetic mechanisms of state-dependent potassium channel inhibition}},
  author = {Efthimios Kyriakis and Agnese Roscioni and Jodene Eldstrom and Daniel Sastre and Ying Dou and Alice Taddei and Steven Molinarolo and Michael Tian and Luca Maragliano and Filip Van Petegem and David Fedida},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aef8456},
  url = {https://www.science.org/doi/10.1126/sciadv.aef8456},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Structural and kinetic mechanisms of state-dependent potassium channel inhibition
AU  - Efthimios Kyriakis
AU  - Agnese Roscioni
AU  - Jodene Eldstrom
AU  - Daniel Sastre
AU  - Ying Dou
AU  - Alice Taddei
AU  - Steven Molinarolo
AU  - Michael Tian
AU  - Luca Maragliano
AU  - Filip Van Petegem
AU  - David Fedida
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aef8456
UR  - https://www.science.org/doi/10.1126/sciadv.aef8456
AB  - ) channel plays a critical role in cardiac repolarization, while loss- or gain-of-function mutations increase the risk of life-threatening arrythmias and sudden death. Like many channels, KCNQ1 exhibits state-dependent pharmacological properties with inhibitors such as UCL2077 displaying higher potency for intermediate over activated states. Here, we report cryo-EM structures and MD simulations of KCNQ1 in complex with UCL2077 in two activation states. UCL2077 breaks tetrameric symmetry and binds in diagonally opposed protomers in pockets formed by the S5-S6 helices from one protomer and the S6 of an adjacent protomer. UCL2077 binding drives distortion of the S6 helix and causes an allosteric collapse of the pore. Specificity arises via structural configurations in the pore that occur with greater frequency in the intermediate state and are stabilized upon drug binding.
SN  - 2375-2548
ER  -