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- EMDB-38041: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2 -

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Basic information

Entry
Database: EMDB / ID: EMD-38041
Titlehuman KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
Map data
Sample
  • Organelle or cellular component: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 2
    • Protein or peptide: Calmodulin-1
  • Ligand: N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide
KeywordsPotassium voltage-gated channel subfamily KQT member 2 / Ebio1-S1 / MEMBRANE PROTEIN
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
Potassium voltage-gated channel subfamily KQT member 2 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsMa D / Guo J
Funding support China, 2 items
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, 2023-
Header (metadata) releaseJan 17, 2024-
Map releaseJan 17, 2024-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38041.png

Downloads & links

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Map

FileDownload / File: emd_38041.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Contour LevelBy AUTHOR: 0.0032
Minimum - Maximum-0.04079584 - 0.07813664
Average (Standard dev.)0.00024167282 (±0.0025256204)
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_38041_half_map_1.map
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Half map: #2

Fileemd_38041_half_map_2.map
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Sample components

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Entire : human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2

EntireName: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
Components
  • Organelle or cellular component: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 2
    • Protein or peptide: Calmodulin-1
  • Ligand: N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide

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Supramolecule #1: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2

SupramoleculeName: human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium voltage-gated channel subfamily KQT member 2

MacromoleculeName: 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: 73.627812 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 PMYSSQTQTY GAS RLIPPL NQLELLRNLK SKSGLAFRKD PPPEPSPSKG SPCRGPLCGC CPGRSSQKVS LKDRVFSSPR GVAAKGKGSP QAQT VRRSP SADQSLEDSP SKVPKSWSFG DRSRARQAFR IKGAASRQNS EEASLPGEDI VDDKSCPCEF VTEDLTPGLK VSIRA VCVM RFLVSKRKFK ESLRPYDVMD VIEQYSAGHL DMLSRIKSLQ SRVDQIVGRG PAITDKDRTK GPAEAELPED PSMMGR LGK VEKQVLSMEK KLDFLVNIYM QRMGIPPTET EAYFGAKEPE PAPPYHSPED SREHVDRHGC IVKIVRSSSS TGQKNFS VE GGSSGGWSHP QFEK

UniProtKB: Potassium voltage-gated channel subfamily KQT member 2

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Macromolecule #2: Calmodulin-1

MacromoleculeName: Calmodulin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.852545 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK

UniProtKB: Calmodulin-1

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Macromolecule #3: N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide

MacromoleculeName: N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide
type: ligand / ID: 3 / Number of copies: 4 / Formula: 7Q0
Molecular weightTheoretical: 306.334 Da
Chemical component information

ChemComp-7Q0:
N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (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 / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7cr3

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 151312
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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