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- PDB-9ixz: human KCNQ2-CaM-Ebio3 Complex in the Presence of PIP2 -

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Basic information

Entry
Database: PDB / ID: 9ixz
Titlehuman KCNQ2-CaM-Ebio3 Complex in the Presence of PIP2
Components
  • Calmodulin-1
  • Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
KeywordsMEMBRANE PROTEIN / voltage-gated potassium channel
Function / homology
Function and homology information


axon initial segment / Voltage gated Potassium channels / node of Ranvier / CaM pathway / Cam-PDE 1 activation / Interaction between L1 and Ankyrins / voltage-gated monoatomic cation channel activity / Sodium/Calcium exchangers / Calmodulin induced events / ankyrin binding ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / CaM pathway / Cam-PDE 1 activation / Interaction between L1 and Ankyrins / voltage-gated monoatomic cation channel activity / Sodium/Calcium exchangers / Calmodulin induced events / ankyrin binding / 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 / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / action potential / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / catalytic complex / Smooth Muscle Contraction / voltage-gated potassium channel activity / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / cellular response to interferon-beta / Protein methylation / calcium channel inhibitor activity / presynaptic cytosol / Activation of AMPK downstream of NMDARs / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / FCGR3A-mediated IL10 synthesis / calyx of Held / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / adenylate cyclase activator activity / sarcomere / VEGFR2 mediated cell proliferation / regulation of cytokinesis / protein serine/threonine kinase activator activity / VEGFR2 mediated vascular permeability / spindle microtubule / calcium channel regulator activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / Stimuli-sensing channels / RAF activation / Transcriptional activation of mitochondrial biogenesis / response to calcium ion / RAS processing / cellular response to type II interferon / G2/M transition of mitotic cell cycle / long-term synaptic potentiation / spindle pole / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / calcium-dependent protein binding / Signaling by BRAF and RAF1 fusions / Inactivation, recovery and regulation of the phototransduction cascade / Platelet degranulation
Similarity search - Function
Potassium channel, voltage dependent, KCNQ2 / Ankyrin-G binding site / Ankyrin-G binding motif of KCNQ2-3 / Unstructured region on Potassium channel subunit alpha KvLQT2 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / : / EF-hand domain pair / EF-hand, calcium binding motif ...Potassium channel, voltage dependent, KCNQ2 / Ankyrin-G binding site / Ankyrin-G binding motif of KCNQ2-3 / Unstructured region on Potassium channel subunit alpha KvLQT2 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / : / 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 / Ion transport domain / Ion transport protein / EF-hand domain pair
Similarity search - Domain/homology
: / Potassium voltage-gated channel subfamily KQT member 2 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYang, Z. / Guo, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31870724 China
CitationJournal: Nat Chem Biol / Year: 2025
Title: Small molecule inhibits KCNQ channels with a non-blocking mechanism.
Authors: Junnan Li / Zhenni Yang / Shaoying Zhang / Yangliang Ye / Jiangnan He / Yan Zhang / Huayun Han / Wan Kong / Jiangru Liu / Yu Min / Juwen Shen / Lianghe Mei / Zongsheng Chen / Panpan Hou / ...Authors: Junnan Li / Zhenni Yang / Shaoying Zhang / Yangliang Ye / Jiangnan He / Yan Zhang / Huayun Han / Wan Kong / Jiangru Liu / Yu Min / Juwen Shen / Lianghe Mei / Zongsheng Chen / Panpan Hou / Jiangtao Guo / Qiansen Zhang / Huaiyu Yang /
Abstract: Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction ...Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel. Ebio3 also showed efficacy in inhibiting currents of KCNQ2 pathogenic gain-of-function mutations, presenting an avenue for VGIC-targeted therapies. Overall, these findings contribute to the understanding of KCNQ2 inhibition and provide insights into developing selective, non-blocking VGIC inhibitors.
History
DepositionJul 29, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Aug 13, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
B: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
C: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
D: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
E: Calmodulin-1
F: Calmodulin-1
G: Calmodulin-1
H: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)345,11512
Polymers343,6618
Non-polymers1,4544
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2 / KQT-like 2 / Neuroblastoma-specific potassium channel subunit alpha KvLQT2 / Voltage-gated ...KQT-like 2 / Neuroblastoma-specific potassium channel subunit alpha KvLQT2 / Voltage-gated potassium channel subunit Kv7.2


Mass: 69062.742 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: O43526
#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 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#3: Chemical
ChemComp-A1L3D / ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-2-propyl-pentanamide


Mass: 363.402 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H23F2N3O2 / 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: human KCNQ2-CaM-Ebio3 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85131 / Symmetry type: POINT

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