12DK

structure of human KCNQ1-CaM-PIP2 intermediate state

Summary for 12DK

• Entry DOI: 10.2210/pdb12dk/pdb
• EMDB information: 76332
• Descriptor: Potassium voltage-gated channel subfamily KQT member 1, Calmodulin-1, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, ... (4 entities in total)
• Functional Keywords: kcnq1, intermediate state, pip2, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 319699.42

Authors

Cui, C.,Kermani, A.,Sun, J. (deposition date: 2026-03-28, release date: 2026-05-06, Last modification date: 2026-06-17)

Primary citation

Cui, J.,Zhao, L.,Xu, X.,Cui, C.,Duan, R.,Kermani, A.,Shi, J.,Han, L.,Sun, J.,Zou, X.
PIP 2 activation of the cardiac I Ks potassium channel.
Res Sq, 2025

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 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.

PubMed: 41282193
DOI: 10.21203/rs.3.rs-7609003/v1

Experimental method

ELECTRON MICROSCOPY (3.47 Å)