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- EMDB-60982: human KCNQ2-CaM-Ebio3 Complex in the Presence of PIP2 -

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Basic information

Entry
Database: EMDB / ID: EMD-60982
Titlehuman KCNQ2-CaM-Ebio3 Complex in the Presence of PIP2
Map data
Sample
  • Complex: human KCNQ2-CaM-Ebio3 complex
    • Protein or peptide: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
    • Protein or peptide: Calmodulin-1
  • Ligand: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-2-propyl-pentanamide
Keywordsvoltage-gated potassium channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / CaM pathway / voltage-gated monoatomic cation channel activity / Cam-PDE 1 activation / Sodium/Calcium exchangers / ankyrin binding / Calmodulin induced events ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / CaM pathway / voltage-gated monoatomic cation channel activity / Cam-PDE 1 activation / Sodium/Calcium exchangers / ankyrin binding / Calmodulin induced events / 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 / Negative regulation of NMDA receptor-mediated neuronal transmission / calcineurin-mediated signaling / 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 / voltage-gated potassium channel activity / Smooth Muscle Contraction / 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 / protein serine/threonine kinase activator activity / regulation of cytokinesis / VEGFR2 mediated vascular permeability / spindle microtubule / Translocation of SLC2A4 (GLUT4) to the plasma membrane / calcium channel regulator activity / 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 / Platelet degranulation / Inactivation, recovery and regulation of the phototransduction cascade
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYang Z / Guo J
Funding support China, 1 items
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, 2024-
Header (metadata) releaseMar 19, 2025-
Map releaseMar 19, 2025-
UpdateAug 13, 2025-
Current statusAug 13, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60982.png

Downloads & links

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Map

FileDownload / File: emd_60982.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 240 pix.
= 223.2 Å		0.93 Å/pix.
x 240 pix.
= 223.2 Å		0.93 Å/pix.
x 240 pix.
= 223.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0095
Minimum - Maximum-0.028062033 - 0.063928485
Average (Standard dev.)0.00014124891 (±0.0020612227)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 223.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_60982_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_60982_half_map_2.map
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Sample components

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Entire : human KCNQ2-CaM-Ebio3 complex

EntireName: human KCNQ2-CaM-Ebio3 complex
Components
  • Complex: human KCNQ2-CaM-Ebio3 complex
    • Protein or peptide: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
    • Protein or peptide: Calmodulin-1
  • Ligand: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-2-propyl-pentanamide

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Supramolecule #1: human KCNQ2-CaM-Ebio3 complex

SupramoleculeName: human KCNQ2-CaM-Ebio3 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2

MacromoleculeName: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.062742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AGKPPKRNAF YRKLQNFLYN VLERPRGWAF IYHAYVFLLV FSCLVLSVFS TIKEYEKSSE GALYILEIVT IVVFGVEYFV RIWAAGCCC RYRGWRGRLK FARKPFCVID IMVLIASIAV LAAGSQGNVF ATSALRSLRF LQILRMIRMD RRGGTWKLLG S VVYAHSKE ...String:
AGKPPKRNAF YRKLQNFLYN VLERPRGWAF IYHAYVFLLV FSCLVLSVFS TIKEYEKSSE GALYILEIVT IVVFGVEYFV RIWAAGCCC RYRGWRGRLK FARKPFCVID IMVLIASIAV LAAGSQGNVF ATSALRSLRF LQILRMIRMD RRGGTWKLLG S VVYAHSKE LVTAWYIGFL CLILASFLVY LAEKGENDHF DTYADALWWG LITLTTIGYG DKYPQTWNGR LLAATFTLIG VS FFALPAG ILGSGFALKV QEQHRQKHFE KRRNPAAGLI QSAWRFYATN LSRTDLHSTW QYYERTVTVP MYRLIPPLNQ LEL LRNLKS KSGLAFRKDP PPEPSPSQKV SLKDRVFSSP RGVAAKGKGS PQAQTVRRSP SADQSLEDSP SKVPKSWSFG DRSR ARQAF RIKGAASRQN SEEASLPGED IVDDKSCPCE FVTEDLTPGL KVSIRAVCVM RFLVSKRKFK ESLRPYDVMD VIEQY SAGH LDMLSRIKSL QSRVDQIVGR GPAITDKDRT KGPAEAELPE DPSMMGRLGK VEKQVLSMEK KLDFLVNIYM QRMGIP PTE TEAYFGAKEP EPAPPYHSPE DSREHVDRHG CIVKIVRSSS STGQKNFS

UniProtKB: Potassium voltage-gated channel subfamily KQT member 2

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Macromolecule #2: Calmodulin-1

MacromoleculeName: Calmodulin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.852545 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK

UniProtKB: Calmodulin-1

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Macromolecule #3: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-2-pro...

MacromoleculeName: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-2-propyl-pentanamide
type: ligand / ID: 3 / Number of copies: 4 / Formula: A1L3D
Molecular weightTheoretical: 363.402 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 85131
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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