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- EMDB-60981: Human KCNQ2-CaM-Ebio2 Complex in the Presence of PIP2 -

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Basic information

Entry
Database: EMDB / ID: EMD-60981
TitleHuman KCNQ2-CaM-Ebio2 Complex in the Presence of PIP2
Map data
Sample
  • Complex: KCNQ2-Ebio2
    • Protein or peptide: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
    • Protein or peptide: Calmodulin-3
  • Ligand: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-3,3-dimethyl-butanamide
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
Keywordsvoltage-gated potassium channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


transporter inhibitor activity / axon initial segment / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / node of Ranvier / voltage-gated monoatomic cation channel activity / Interaction between L1 and Ankyrins / ankyrin binding / negative regulation of high voltage-gated calcium channel activity ...transporter inhibitor activity / axon initial segment / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / node of Ranvier / voltage-gated monoatomic cation channel activity / Interaction between L1 and Ankyrins / ankyrin binding / negative regulation of high voltage-gated calcium channel activity / response to corticosterone / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / nitric-oxide synthase binding / regulation of cell communication by electrical coupling involved in cardiac conduction / regulation of synaptic vesicle exocytosis / calcineurin-mediated signaling / action potential / adenylate cyclase binding / protein phosphatase activator activity / catalytic complex / voltage-gated potassium channel activity / regulation of synaptic vesicle endocytosis / detection of calcium ion / regulation of cardiac muscle contraction / postsynaptic cytosol / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / phosphatidylinositol 3-kinase binding / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / regulation of heart rate / calyx of Held / response to amphetamine / adenylate cyclase activator activity / sarcomere / nitric-oxide synthase regulator activity / protein serine/threonine kinase activator activity / regulation of cytokinesis / spindle microtubule / calcium channel regulator activity / response to calcium ion / mitochondrial membrane / Schaffer collateral - CA1 synapse / G2/M transition of mitotic cell cycle / long-term synaptic potentiation / spindle pole / calcium-dependent protein binding / synaptic vesicle membrane / nervous system development / myelin sheath / growth cone / vesicle / chemical synaptic transmission / transmembrane transporter binding / calmodulin binding / G protein-coupled receptor signaling pathway / protein domain specific binding / calcium ion binding / synapse / centrosome / protein kinase binding / protein-containing complex / nucleus / membrane / plasma membrane / cytoplasm
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-3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 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_60981.png

Downloads & links

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Map

FileDownload / File: emd_60981.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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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
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0085
Minimum - Maximum-0.042502288 - 0.08348336
Average (Standard dev.)0.00010648362 (±0.0026013749)
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_60981_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Half map: #2

Fileemd_60981_half_map_2.map
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Sample components

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Entire : KCNQ2-Ebio2

EntireName: KCNQ2-Ebio2
Components
  • Complex: KCNQ2-Ebio2
    • Protein or peptide: Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
    • Protein or peptide: Calmodulin-3
  • Ligand: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-3,3-dimethyl-butanamide
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Supramolecule #1: KCNQ2-Ebio2

SupramoleculeName: KCNQ2-Ebio2 / 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: 70.880742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGKPPKRNA FYRKLQNFLY NVLERPRGWA FIYHAYVFLL VFSCLVLSVF STIKEYEKSS EGALYILEIV TIVVFGVEYF VRIWAAGCC CRYRGWRGRL KFARKPFCVI DIMVLIASIA VLAAGSQGNV FATSALRSLR FLQILRMIRM DRRGGTWKLL G SVVYAHSK ...String:
MAGKPPKRNA FYRKLQNFLY NVLERPRGWA FIYHAYVFLL VFSCLVLSVF STIKEYEKSS EGALYILEIV TIVVFGVEYF VRIWAAGCC CRYRGWRGRL KFARKPFCVI DIMVLIASIA VLAAGSQGNV FATSALRSLR FLQILRMIRM DRRGGTWKLL G SVVYAHSK ELVTAWYIGF LCLILASFLV YLAEKGENDH FDTYADALWW GLITLTTIGY GDKYPQTWNG RLLAATFTLI GV SFFALPA GILGSGFALK VQEQHRQKHF EKRRNPAAGL IQSAWRFYAT NLSRTDLHST WQYYERTVTV PMYRLIPPLN QLE LLRNLK SKSGLAFRKD PPPEPSPSQK VSLKDRVFSS PRGVAAKGKG SPQAQTVRRS PSADQSLEDS PSKVPKSWSF GDRS RARQA FRIKGAASRQ NSEEASLPGE DIVDDKSCPC EFVTEDLTPG LKVSIRAVCV MRFLVSKRKF KESLRPYDVM DVIEQ YSAG HLDMLSRIKS LQSRVDQIVG RGPAITDKDR TKGPAEAELP EDPSMMGRLG KVEKQVLSME KKLDFLVNIY MQRMGI PPT ETEAYFGAKE PEPAPPYHSP EDSREHVDRH GCIVKIVRSS SSTGQKNFSL EGGSSGGWSH PQFEK

UniProtKB: Potassium voltage-gated channel subfamily KQT member 2

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Macromolecule #2: Calmodulin-3

MacromoleculeName: Calmodulin-3 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.615445 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK LEGGSSGGLV P RGSGGSSG GHHHHHHHH

UniProtKB: Calmodulin-3

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

MacromoleculeName: ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-3,3-dimethyl-butanamide
type: ligand / ID: 3 / Number of copies: 4 / Formula: A1L3C
Molecular weightTheoretical: 335.348 Da

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Macromolecule #4: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
type: ligand / ID: 4 / Number of copies: 4 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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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

MicroscopeTFS 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 74947
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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