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- PDB-8x43: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2 -

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Basic information

Entry
Database: PDB / ID: 8x43
Titlehuman KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
Components
  • Calmodulin-1
  • Potassium voltage-gated channel subfamily KQT member 2
KeywordsMEMBRANE PROTEIN / Potassium voltage-gated channel subfamily KQT member 2 / Ebio1-S1
Function / homology
Function and homology information


axon initial segment / Voltage gated Potassium channels / node of Ranvier / voltage-gated monoatomic cation channel activity / CaM pathway / Cam-PDE 1 activation / Interaction between L1 and Ankyrins / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / voltage-gated monoatomic cation channel activity / CaM pathway / Cam-PDE 1 activation / Interaction between L1 and Ankyrins / Sodium/Calcium exchangers / 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 / ankyrin binding / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / presynaptic endocytosis / regulation of cardiac muscle cell action potential / negative regulation of peptidyl-threonine phosphorylation / calcineurin-mediated signaling / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Synthesis of IP3 and IP4 in the cytosol / negative regulation of ryanodine-sensitive calcium-release channel activity / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / protein phosphatase activator activity / Long-term potentiation / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / regulation of ryanodine-sensitive calcium-release channel activity / DARPP-32 events / voltage-gated potassium channel activity / action potential / catalytic complex / Smooth Muscle Contraction / regulation of cardiac muscle contraction / detection of calcium ion / RHO GTPases activate IQGAPs / calcium channel inhibitor activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / cellular response to interferon-beta / Protein methylation / Activation of AMPK downstream of NMDARs / positive regulation of protein autophosphorylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / eNOS activation / regulation of calcium-mediated signaling / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / voltage-gated potassium channel complex / sperm midpiece / calcium channel complex / potassium ion transmembrane transport / substantia nigra development / positive regulation of peptidyl-threonine phosphorylation / calyx of Held / FCERI mediated Ca+2 mobilization / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / FCGR3A-mediated IL10 synthesis / regulation of heart rate / sarcomere / protein serine/threonine kinase activator activity / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / regulation of cytokinesis / VEGFR2 mediated cell proliferation / VEGFR2 mediated vascular permeability / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of protein serine/threonine kinase activity / spindle microtubule / positive regulation of receptor signaling pathway via JAK-STAT / RAF activation / Transcriptional activation of mitochondrial biogenesis / Stimuli-sensing channels / cellular response to type II interferon / spindle pole / response to calcium ion / calcium-dependent protein binding / RAS processing / 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 / G2/M transition of mitotic cell cycle
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-7Q0 / Potassium voltage-gated channel subfamily KQT member 2 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsMa, D. / Guo, J.
Funding support China, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0908501 China
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
CitationJournal: Nat Chem Biol / Year: 2024
Title: A small-molecule activation mechanism that directly opens the KCNQ2 channel.
Authors: Shaoying Zhang / Demin Ma / Kun Wang / Ya Li / Zhenni Yang / Xiaoxiao Li / Junnan Li / Jiangnan He / Lianghe Mei / Yangliang Ye / Zongsheng Chen / Juwen Shen / Panpan Hou / Jiangtao Guo / ...Authors: Shaoying Zhang / Demin Ma / Kun Wang / Ya Li / Zhenni Yang / Xiaoxiao Li / Junnan Li / Jiangnan He / Lianghe Mei / Yangliang Ye / Zongsheng Chen / Juwen Shen / Panpan Hou / Jiangtao Guo / Qiansen Zhang / Huaiyu Yang /
Abstract: Pharmacological activation of voltage-gated ion channels by ligands serves as the basis for therapy and mainly involves a classic gating mechanism that augments the native voltage-dependent open ...Pharmacological activation of voltage-gated ion channels by ligands serves as the basis for therapy and mainly involves a classic gating mechanism that augments the native voltage-dependent open probability. Through structure-based virtual screening, we identified a new scaffold compound, Ebio1, serving as a potent and subtype-selective activator for the voltage-gated potassium channel KCNQ2 and featuring a new activation mechanism. Single-channel patch-clamp, cryogenic-electron microscopy and molecular dynamic simulations, along with chemical derivatives, reveal that Ebio1 engages the KCNQ2 activation by generating an extended channel gate with a larger conductance at the saturating voltage (+50 mV). This mechanism is different from the previously observed activation mechanism of ligands on voltage-gated ion channels. Ebio1 caused S6 helices from residues S303 and F305 to perform a twist-to-open movement, which was sufficient to open the KCNQ2 gate. Overall, our findings provide mechanistic insights into the activation of KCNQ2 channel by Ebio1 and lend support for KCNQ-related drug development.
History
DepositionNov 15, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 2
B: Calmodulin-1
C: Potassium voltage-gated channel subfamily KQT member 2
D: Calmodulin-1
E: Potassium voltage-gated channel subfamily KQT member 2
F: Calmodulin-1
G: Potassium voltage-gated channel subfamily KQT member 2
H: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)363,14712
Polymers361,9218
Non-polymers1,2254
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
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: 73627.812 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ2 / Production host: Homo sapiens (human) / References: UniProt: O43526
#2: Protein
Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#3: Chemical
ChemComp-7Q0 / N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide


Mass: 306.334 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H15FN2O / Feature type: SUBJECT OF INVESTIGATION
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: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151312 / Symmetry type: POINT

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