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- PDB-12dk: structure of human KCNQ1-CaM-PIP2 intermediate state -

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Basic information

Entry
Database: PDB / ID: 12dk
Titlestructure of human KCNQ1-CaM-PIP2 intermediate state
Components
  • Calmodulin-1
  • Potassium voltage-gated channel subfamily KQT member 1
KeywordsMEMBRANE PROTEIN / KCNQ1 / intermediate state / PIP2
Function / homology
Function and homology information


gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / negative regulation of voltage-gated potassium channel activity / basolateral part of cell / lumenal side of membrane / negative regulation of delayed rectifier potassium channel activity / rhythmic behavior / stomach development / regulation of gastric acid secretion ...gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / negative regulation of voltage-gated potassium channel activity / basolateral part of cell / lumenal side of membrane / negative regulation of delayed rectifier potassium channel activity / rhythmic behavior / stomach development / regulation of gastric acid secretion / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / Phase 3 - rapid repolarisation / membrane repolarization during action potential / membrane repolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / iodide transport / regulation of atrial cardiac muscle cell membrane repolarization / membrane repolarization during ventricular cardiac muscle cell action potential / intracellular chloride ion homeostasis / potassium ion export across plasma membrane / membrane repolarization during cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / atrial cardiac muscle cell action potential / regulation of membrane repolarization / renal sodium ion absorption / auditory receptor cell development / protein phosphatase 1 binding / detection of mechanical stimulus involved in sensory perception of sound / delayed rectifier potassium channel activity / ventricular cardiac muscle cell action potential / potassium ion homeostasis / regulation of ventricular cardiac muscle cell membrane repolarization / positive regulation of potassium ion transmembrane transport / Voltage gated Potassium channels / non-motile cilium assembly / outward rectifier potassium channel activity / intestinal absorption / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / inner ear morphogenesis / cardiac muscle cell contraction / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / adrenergic receptor signaling pathway / negative regulation of high voltage-gated calcium channel activity / PKA activation / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / renal absorption / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / Activation of RAC1 downstream of NMDARs / : / autophagosome membrane docking / protein kinase A regulatory subunit binding / ciliary base / protein kinase A catalytic subunit binding / negative regulation of calcium ion export across plasma membrane / regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle cell action potential / regulation of heart contraction / presynaptic endocytosis / inner ear development / Synthesis of IP3 and IP4 in the cytosol / potassium ion import across plasma membrane / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcineurin-mediated signaling / regulation of heart rate by cardiac conduction / regulation of cell communication by electrical coupling involved in cardiac conduction / monoatomic ion channel complex / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / cochlea development / protein phosphatase activator activity / Long-term potentiation / Calcineurin activates NFAT / action potential / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / voltage-gated potassium channel activity / detection of calcium ion / social behavior / regulation of cardiac muscle contraction / catalytic complex / positive regulation of heart rate / RHO GTPases activate IQGAPs / transport vesicle / calcium channel inhibitor activity / presynaptic cytosol / Activation of AMPK downstream of NMDARs
Similarity search - Function
Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. ...Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Chem-PT5 / Calmodulin-1 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsCui, C. / Kermani, A. / Sun, J.
Funding support United States, Singapore, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL155398 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL166628 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R35GM136409 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)2R35GM136409 United States
Ministry of Education (MoE, Singapore)A-8002958-00-00 Singapore
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R00HL143037 United States
CitationJournal: Res Sq / Year: 2025
Title: PIP activation of the cardiac I potassium channel.
Authors: Jianmin Cui / Lu Zhao / Xianjin Xu / Chenxi Cui / Rui Duan / Ali Kermani / Jingyi Shi / Lu Han / Ji Sun / Xiaoqin Zou /
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.
History
DepositionMar 28, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2026Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 1
B: Calmodulin-1
D: Calmodulin-1
F: Calmodulin-1
H: Calmodulin-1
C: Potassium voltage-gated channel subfamily KQT member 1
E: Potassium voltage-gated channel subfamily KQT member 1
G: Potassium voltage-gated channel subfamily KQT member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)319,69920
Polymers315,1908
Non-polymers4,50912
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Potassium voltage-gated channel subfamily KQT member 1 / IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1 / KQT-like 1 / Voltage- ...IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1 / KQT-like 1 / Voltage-gated potassium channel subunit Kv7.1


Mass: 61945.066 Da / Num. of mol.: 4 / Mutation: I145C, E160R, R231E
Source method: isolated from a genetically manipulated source
Details: 76-620 reserved / Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ1, KCNA8, KCNA9, KVLQT1 / Production host: Homo sapiens (human) / References: UniProt: P51787
#2: Protein
Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#3: Chemical
ChemComp-PT5 / [(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 / Phosphatidylinositol 4,5-bisphosphate / PtdIns(4,5)P2


Mass: 1047.088 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C47H85O19P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: KCNQ1-CaM-PIP2 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 161967 / Symmetry type: POINT
RefinementHighest resolution: 3.47 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315772
ELECTRON MICROSCOPYf_angle_d0.56721300
ELECTRON MICROSCOPYf_dihedral_angle_d8.3232184
ELECTRON MICROSCOPYf_chiral_restr0.0342396
ELECTRON MICROSCOPYf_plane_restr0.0032648

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