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- PDB-7vnp: Structure of human KCNQ4-ML213 complex with PIP2 -

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Basic information

Entry
Database: PDB / ID: 7vnp
TitleStructure of human KCNQ4-ML213 complex with PIP2
Components
  • Calmodulin-3
  • Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
KeywordsMEMBRANE PROTEIN / KCNQ4 / ML213 / PIP2 / cryo-EM
Function / homology
Function and homology information


CASP4 inflammasome assembly / transporter inhibitor activity / : / type 3 metabotropic glutamate receptor binding / Voltage gated Potassium channels / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / Enterobacterial factors antagonize host defense / response to corticosterone / negative regulation of high voltage-gated calcium channel activity ...CASP4 inflammasome assembly / transporter inhibitor activity / : / type 3 metabotropic glutamate receptor binding / Voltage gated Potassium channels / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / Enterobacterial factors antagonize host defense / response to corticosterone / negative regulation of high voltage-gated calcium channel activity / regulation of synaptic vesicle exocytosis / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / calcineurin-mediated signaling / nitric-oxide synthase binding / regulation of cell communication by electrical coupling involved in cardiac conduction / adenylate cyclase binding / protein phosphatase activator activity / regulation of synaptic vesicle endocytosis / potassium ion transport / carbohydrate transmembrane transporter activity / voltage-gated potassium channel activity / potassium channel activity / catalytic complex / maltose binding / detection of calcium ion / maltose transport / maltodextrin transmembrane transport / postsynaptic cytosol / regulation of cardiac muscle contraction / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / phosphatidylinositol 3-kinase binding / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / voltage-gated potassium channel complex / sensory perception of sound / calcium channel complex / substantia nigra development / regulation of heart rate / potassium ion transmembrane transport / response to amphetamine / calyx of Held / basal plasma membrane / nitric-oxide synthase regulator activity / adenylate cyclase activator activity / protein serine/threonine kinase activator activity / regulation of cytokinesis / spindle microtubule / sarcomere / calcium channel regulator activity / myelin sheath / response to calcium ion / long-term synaptic potentiation / Schaffer collateral - CA1 synapse / mitochondrial membrane / spindle pole / sperm midpiece / calcium-dependent protein binding / synaptic vesicle membrane / outer membrane-bounded periplasmic space / growth cone / vesicle / transmembrane transporter binding / G protein-coupled receptor signaling pathway / protein domain specific binding / centrosome / calcium ion binding / protein kinase binding / chromatin / protein-containing complex / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / EF-hand / Bacterial extracellular solute-binding protein / Recoverin; domain 1 / : ...Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / EF-hand / Bacterial extracellular solute-binding protein / Recoverin; domain 1 / : / Bacterial extracellular solute-binding protein / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7YV / : / Chem-PT5 / Maltodextrin-binding protein / Calmodulin-3 / Potassium voltage-gated channel subfamily KQT member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsXu, F. / Zheng, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0507000 China
CitationJournal: Neuron / Year: 2022
Title: Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel.
Authors: You Zheng / Heng Liu / Yuxin Chen / Shaowei Dong / Fang Wang / Shengyi Wang / Geng-Lin Li / Yilai Shu / Fei Xu /
Abstract: The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on ...The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on the signaling lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2). However, the molecular mechanism of PIP2 in modulating the opening of the four neuronal KCNQ channels (KCNQ2-KCNQ5), which are essential for regulating neuronal excitability, remains largely elusive. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 determined in complex with the activator ML213 in the absence or presence of PIP2. Two PIP2 molecules are identified in the open-state structure of KCNQ4, which act as a bridge to couple the voltage-sensing domain (VSD) and pore domain (PD) of KCNQ4 leading to the channel opening. Our findings reveal the binding sites and activation mechanisms of ML213 and PIP2 for neuronal KCNQ channels, providing a framework for therapeutic intervention targeting on these important channels.
History
DepositionOct 11, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.0Dec 1, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 1, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Dec 1, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 1, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 1, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Feb 16, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.3Jul 2, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
B: Calmodulin-3
C: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
D: Calmodulin-3
E: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
F: Calmodulin-3
G: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
H: Calmodulin-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)543,13824
Polymers533,5768
Non-polymers9,56316
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein / KQT-like 4 / Potassium channel subunit alpha KvLQT4 / Voltage-gated potassium channel subunit Kv7.4


Mass: 116541.383 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: The fusion protein of Potassium voltage-gated channel subfamily KQT member 4, linker, and Maltodextrin-binding protein
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (strain B / BL21-DE3) (bacteria)
Gene: KCNQ4, ECBD_4002 / Strain: B / BL21-DE3 / Production host: Homo sapiens (human) / References: UniProt: P56696, UniProt: A0A140NCD0
#2: Protein
Calmodulin-3


Mass: 16852.545 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 / Production host: Homo sapiens (human) / References: UniProt: P0DP25
#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.: 8 / Source method: obtained synthetically / Formula: C47H85O19P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#4: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#5: Chemical
ChemComp-7YV / (1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid


Mass: 257.371 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H23NO
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: KCNQ4-ML213 complex with 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
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: DARK FIELD
Image recordingElectron dose: 16.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 133661 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0114428
ELECTRON MICROSCOPYf_angle_d0.8719580
ELECTRON MICROSCOPYf_dihedral_angle_d25.5942068
ELECTRON MICROSCOPYf_chiral_restr0.0482244
ELECTRON MICROSCOPYf_plane_restr0.0042456

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