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| Title | PIP activation of the cardiac I potassium channel. |
|---|---|
| Journal, issue, pages | Res Sq, Year 2025 |
| Publish date | Oct 21, 2025 |
Authors | Jianmin Cui / Lu Zhao / Xianjin Xu / Chenxi Cui / Rui Duan / Ali Kermani / Jingyi Shi / Lu Han / Ji Sun / Xiaoqin Zou / ![]() |
| PubMed Abstract | The I channel complex, composed of the voltage-gated potassium channel KCNQ1 and its regulatory subunit KCNE1, is essential for the termination of cardiac action potentials. The function of KCNQ1 and ...The I channel complex, composed of the voltage-gated potassium channel KCNQ1 and its regulatory subunit KCNE1, is essential for the termination of cardiac action potentials. The function of KCNQ1 and I requires PIP, and its depletion abolishes channel opening. Previous studies revealed that KCNQ1 adopts both bent and straight conformations and can bind two PIP molecules: one adjacent to VSD (V-PIP), and the other at the VSD-pore interface (C-PIP). Here we show that the two PIP perform essential yet distinct roles: V-PIP enables the bent-to-straight transition, whereas C-PIP mediates VSD-pore coupling and stabilizes the straight conformation. Structure-function analysis and molecular dynamic simulations show that VSD activation elevates the V-PIP site and weakens the CaM-VSD interaction, permitting the conformational shift from the bent, intermediate open (IO) state associated with KCNQ1 to the straight, I-exclusive activated open (AO) state, which is further stabilized by C-PIP. Leveraging this mechanism, we developed a compound CA1, which selectively targets the V-PIP site and modulates I channel activity without affecting KCNQ1, offering a novel and promising conceptional path for specific and safe antiarrhythmic therapeutics. |
External links | Res Sq / PubMed:41282193 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.47 Å |
| Structure data | EMDB-76332, PDB-12dk: |
| Chemicals | ![]() ChemComp-PT5: ![]() ChemComp-CA: |
| Source |
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Keywords | MEMBRANE PROTEIN / KCNQ1 / intermediate state / PIP2 |
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homo sapiens (human)
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