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- EMDB-35877: Human KCNQ2-CaM in complex with HN37 -

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Basic information

Entry
Database: EMDB / ID: EMD-35877
TitleHuman KCNQ2-CaM in complex with HN37
Map data
Sample
  • Complex: human KCNQ2-CaM in complex with HN37
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 2
  • Ligand: methyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]-2,6-dimethyl-phenyl]carbamate
Keywordspotassium voltage-gated channel / HN37 / MEMBRANE PROTEIN
Function / homology
Function and homology information


axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / ankyrin binding / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / nervous system development / chemical synaptic transmission ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / ankyrin binding / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / nervous system development / chemical synaptic transmission / calmodulin binding / synapse / plasma membrane
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 / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Potassium voltage-gated channel subfamily KQT member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsMa D / Li X / Guo J
Funding support China, 4 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0908501 China
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
National Natural Science Foundation of China (NSFC)81825021 China
National Natural Science Foundation of China (NSFC)92169202 China
CitationJournal: Nat Commun / Year: 2023
Title: Ligand activation mechanisms of human KCNQ2 channel.
Authors: Demin Ma / Yueming Zheng / Xiaoxiao Li / Xiaoyu Zhou / Zhenni Yang / Yan Zhang / Long Wang / Wenbo Zhang / Jiajia Fang / Guohua Zhao / Panpan Hou / Fajun Nan / Wei Yang / Nannan Su / ...Authors: Demin Ma / Yueming Zheng / Xiaoxiao Li / Xiaoyu Zhou / Zhenni Yang / Yan Zhang / Long Wang / Wenbo Zhang / Jiajia Fang / Guohua Zhao / Panpan Hou / Fajun Nan / Wei Yang / Nannan Su / Zhaobing Gao / Jiangtao Guo /
Abstract: The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but ...The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2.
History
DepositionApr 9, 2023-
Header (metadata) releaseNov 29, 2023-
Map releaseNov 29, 2023-
UpdateNov 29, 2023-
Current statusNov 29, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35877.png

Downloads & links

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Map

FileDownload / File: emd_35877.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.014 Å
Density
Contour LevelBy AUTHOR: 0.0181
Minimum - Maximum-0.07320697 - 0.14510565
Average (Standard dev.)-0.00006142554 (±0.0042349715)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 243.36002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35877_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_35877_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : human KCNQ2-CaM in complex with HN37

EntireName: human KCNQ2-CaM in complex with HN37
Components
  • Complex: human KCNQ2-CaM in complex with HN37
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 2
  • Ligand: methyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]-2,6-dimethyl-phenyl]carbamate

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Supramolecule #1: human KCNQ2-CaM in complex with HN37

SupramoleculeName: human KCNQ2-CaM in complex with HN37 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: methyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]-2,6-dimeth...

MacromoleculeName: methyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]-2,6-dimethyl-phenyl]carbamate
type: ligand / ID: 2 / Number of copies: 8 / Formula: 9MF
Molecular weightTheoretical: 340.391 Da
Chemical component information

ChemComp-9MF:
methyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]-2,6-dimethyl-phenyl]carbamate

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.3 µm / Nominal defocus min: 1.1 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2
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

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 367290

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