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- EMDB-13605: Ligand-bound human Kv3.1 cryo-EM structure (Lu AG00563) -

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Basic information

Entry
Database: EMDB / ID: EMD-13605
TitleLigand-bound human Kv3.1 cryo-EM structure (Lu AG00563)
Map data
Sample
  • Complex: Detergent solubilized tetramer of human Kv3.1 potassium ion channel in complex with Lu AG00563
    • Protein or peptide: Potassium voltage-gated channel subfamily C member 1
  • Ligand: 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide
  • Ligand: POTASSIUM ION
  • Ligand: water
KeywordsPotassium ion channel / voltage gated / drug target / MEMBRANE PROTEIN
Function / homology
Function and homology information


response to nerve growth factor / globus pallidus development / response to fibroblast growth factor / response to potassium ion / corpus callosum development / response to auditory stimulus / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / delayed rectifier potassium channel activity / Voltage gated Potassium channels / positive regulation of potassium ion transmembrane transport ...response to nerve growth factor / globus pallidus development / response to fibroblast growth factor / response to potassium ion / corpus callosum development / response to auditory stimulus / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / delayed rectifier potassium channel activity / Voltage gated Potassium channels / positive regulation of potassium ion transmembrane transport / response to light intensity / optic nerve development / neuronal cell body membrane / response to amine / action potential / axolemma / kinesin binding / voltage-gated potassium channel activity / axon terminus / voltage-gated potassium channel complex / potassium ion transmembrane transport / dendrite membrane / calyx of Held / cerebellum development / protein tetramerization / protein homooligomerization / potassium ion transport / response to toxic substance / cellular response to xenobiotic stimulus / presynaptic membrane / transmembrane transporter binding / postsynaptic membrane / cell surface / plasma membrane
Similarity search - Function
Potassium channel, voltage dependent, Kv3.1 / Potassium channel, voltage dependent, Kv3 / Potassium channel, voltage dependent, Kv / Potassium channel tetramerisation-type BTB domain / BTB/POZ domain / Voltage-gated potassium channel / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / Voltage-dependent channel domain superfamily / SKP1/BTB/POZ domain superfamily ...Potassium channel, voltage dependent, Kv3.1 / Potassium channel, voltage dependent, Kv3 / Potassium channel, voltage dependent, Kv / Potassium channel tetramerisation-type BTB domain / BTB/POZ domain / Voltage-gated potassium channel / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / Voltage-dependent channel domain superfamily / SKP1/BTB/POZ domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Voltage-gated potassium channel KCNC1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsBotte M / Huber S / Bucher D / Klint JK / Rodriguez D / Tagmose L / Chami M / Cheng R / Hennig M / Abdul Rhaman W
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: PNAS Nexus / Year: 2022
Title: Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators.
Authors: Mathieu Botte / Sophie Huber / Denis Bucher / Julie K Klint / David Rodríguez / Lena Tagmose / Mohamed Chami / Robert Cheng / Michael Hennig / Wassim Abdul Rahman /
Abstract: Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with ...Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders.
History
DepositionSep 20, 2021-
Header (metadata) releaseAug 17, 2022-
Map releaseAug 17, 2022-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_13605.png

Downloads & links

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Map

FileDownload / File: emd_13605.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 340 pix.
= 278.8 Å		0.82 Å/pix.
x 340 pix.
= 278.8 Å		0.82 Å/pix.
x 340 pix.
= 278.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.341
Minimum - Maximum-1.8955537 - 3.2902455
Average (Standard dev.)0.0026736606 (±0.053391688)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 278.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Detergent solubilized tetramer of human Kv3.1 potassium ion chann...

EntireName: Detergent solubilized tetramer of human Kv3.1 potassium ion channel in complex with Lu AG00563
Components
  • Complex: Detergent solubilized tetramer of human Kv3.1 potassium ion channel in complex with Lu AG00563
    • Protein or peptide: Potassium voltage-gated channel subfamily C member 1
  • Ligand: 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide
  • Ligand: POTASSIUM ION
  • Ligand: water

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Supramolecule #1: Detergent solubilized tetramer of human Kv3.1 potassium ion chann...

SupramoleculeName: Detergent solubilized tetramer of human Kv3.1 potassium ion channel in complex with Lu AG00563
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 C member 1

MacromoleculeName: Potassium voltage-gated channel subfamily C member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.88318 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGQGDESERI VINVGGTRHQ TYRSTLRTLP GTRLAWLAEP DAHSHFDYDP RADEFFFDRH PGVFAHILNY YRTGKLHCPA DVCGPLYEE ELAFWGIDET DVEPCCWMTY RQHRDAEEAL DSFGGAPLDN SADDADADGP GDSGDGEDEL EMTKRLALSD S PDGRPGGF ...String:
MGQGDESERI VINVGGTRHQ TYRSTLRTLP GTRLAWLAEP DAHSHFDYDP RADEFFFDRH PGVFAHILNY YRTGKLHCPA DVCGPLYEE ELAFWGIDET DVEPCCWMTY RQHRDAEEAL DSFGGAPLDN SADDADADGP GDSGDGEDEL EMTKRLALSD S PDGRPGGF WRRWQPRIWA LFEDPYSSRY ARYVAFASLF FILVSITTFC LETHERFNPI VNKTEIENVR NGTQVRYYRE AE TEAFLTY IEGVCVVWFT FEFLMRVIFC PNKVEFIKNS LNIIDFVAIL PFYLEVGLSG LSSKAAKDVL GFLRVVRFVR ILR IFKLTR HFVGLRVLGH TLRASTNEFL LLIIFLALGV LIFATMIYYA ERIGAQPNDP SASEHTHFKN IPIGFWWAVV TMTT LGYGD MYPQTWSGML VGALCALAGV LTIAMPVPVI VNNFGMYYSL AMAKQKLPKK KKKHIPRPPQ LGSPNYCKSV VNSPH HSTQ SDTCPLAQEE ILEINRAGRK PLRGMSIGSL EVLFQ

UniProtKB: Voltage-gated potassium channel KCNC1

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Macromolecule #2: 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-car...

MacromoleculeName: 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: 805
Molecular weightTheoretical: 345.373 Da
Chemical component information

ChemComp-805:
1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide

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Macromolecule #3: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 14 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 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:

2a79

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 219839
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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