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- PDB-9ixy: Human KCNQ2-CaM-Ebio2 Complex in the Presence of PIP2 -

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Basic information

Entry
Database: PDB / ID: 9ixy
TitleHuman KCNQ2-CaM-Ebio2 Complex in the Presence of PIP2
Components
  • Calmodulin-3
  • Isoform 3 of Potassium voltage-gated channel subfamily KQT member 2
KeywordsMEMBRANE PROTEIN / voltage-gated potassium channel
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 / response to corticosterone ...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 / response to corticosterone / negative regulation of high voltage-gated calcium channel activity / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / nitric-oxide synthase binding / regulation of synaptic vesicle exocytosis / regulation of cell communication by electrical coupling involved in cardiac conduction / calcineurin-mediated signaling / adenylate cyclase binding / action potential / protein phosphatase activator activity / voltage-gated potassium channel activity / catalytic complex / detection of calcium ion / regulation of synaptic vesicle endocytosis / 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 / G2/M transition of mitotic cell cycle / Schaffer collateral - CA1 synapse / long-term synaptic potentiation / spindle pole / calcium-dependent protein binding / synaptic vesicle membrane / nervous system development / myelin sheath / growth cone / chemical synaptic transmission / vesicle / 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
: / Chem-PIO / Potassium voltage-gated channel subfamily KQT member 2 / Calmodulin-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 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 1.1Apr 2, 2025Group: Data collection / Source and taxonomy / Category: em_admin / entity_src_gen
Item: _em_admin.last_update / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.1Apr 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Experimental summary / Source and taxonomy / Data content type: EM metadata / EM metadata / Category: em_admin / entity_src_gen / Data content type: EM metadata / EM metadata / EM metadata
Item: _em_admin.last_update / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.2Aug 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-3
F: Calmodulin-3
G: Calmodulin-3
H: Calmodulin-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)366,31216
Polymers361,9858
Non-polymers4,3288
Water00
1


  • Idetical with deposited unit
  • defined by author
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: 70880.742 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-3


Mass: 19615.445 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM3, CALML2, CAM3, CAMC, CAMIII / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P0DP25
#3: Chemical
ChemComp-A1L3C / ~{N}-[7-[bis(fluoranyl)methoxy]-1-prop-2-ynyl-indazol-3-yl]-3,3-dimethyl-butanamide


Mass: 335.348 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H19F2N3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
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 / dioctanoyl l-alpha-phosphatidyl-d-myo-inositol 4,5-diphosphate


Mass: 746.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H49O19P3 / 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: KCNQ2-Ebio2 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: hek 293
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: TFS 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 74947 / Symmetry type: POINT

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