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- PDB-7vnr: Structure of human KCNQ4-ML213 complex in digitonin -

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Basic information

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


transporter inhibitor activity / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / inner ear morphogenesis / negative regulation of high voltage-gated calcium channel activity / response to corticosterone / negative regulation of calcium ion export across plasma membrane ...transporter inhibitor activity / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / inner ear morphogenesis / 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 / calcineurin-mediated signaling / regulation of synaptic vesicle exocytosis / protein phosphatase activator activity / adenylate cyclase binding / voltage-gated potassium channel activity / catalytic complex / carbohydrate transmembrane transporter activity / regulation of synaptic vesicle endocytosis / maltose binding / detection of calcium ion / maltose transport / potassium channel activity / regulation of cardiac muscle contraction / maltodextrin transmembrane transport / postsynaptic cytosol / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / phosphatidylinositol 3-kinase binding / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / voltage-gated potassium channel complex / regulation of calcium-mediated signaling / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / response to amphetamine / calcium channel regulator activity / regulation of heart rate / nitric-oxide synthase regulator activity / basal plasma membrane / calyx of Held / adenylate cyclase activator activity / sarcomere / regulation of cytokinesis / protein serine/threonine kinase activator activity / spindle microtubule / sensory perception of sound / mitochondrial membrane / potassium ion transport / Schaffer collateral - CA1 synapse / long-term synaptic potentiation / response to calcium ion / spindle pole / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / synaptic vesicle membrane / myelin sheath / outer membrane-bounded periplasmic space / growth cone / vesicle / transmembrane transporter binding / G protein-coupled receptor signaling pathway / protein domain specific binding / calcium ion binding / centrosome / protein kinase binding / protein-containing complex / nucleus / plasma membrane / 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. / Bacterial extracellular solute-binding protein / EF-hand / : / Bacterial extracellular solute-binding protein ...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. / Bacterial extracellular solute-binding protein / EF-hand / : / Bacterial extracellular solute-binding protein / Recoverin; domain 1 / 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 / : / 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: 2.8 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 1.1Feb 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)534,72215
Polymers533,5768
Non-polymers1,1477
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-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
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K
Has ligand of interestY

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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 in digitonin / 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.: 4.8 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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 126225 / Symmetry type: POINT

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