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- PDB-7pqu: Ligand-bound human Kv3.1 cryo-EM structure (Lu AG00563) -

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Basic information

Entry
Database: PDB / ID: 7pqu
TitleLigand-bound human Kv3.1 cryo-EM structure (Lu AG00563)
ComponentsPotassium voltage-gated channel subfamily C member 1
KeywordsMEMBRANE PROTEIN / Potassium ion channel / voltage gated / drug target
Function / homology
Function and homology information


response to nerve growth factor / globus pallidus development / response to auditory stimulus / response to fibroblast growth factor / response to potassium ion / corpus callosum development / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of potassium ion transmembrane transport / delayed rectifier potassium channel activity / Voltage gated Potassium channels ...response to nerve growth factor / globus pallidus development / response to auditory stimulus / response to fibroblast growth factor / response to potassium ion / corpus callosum development / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of potassium ion transmembrane transport / delayed rectifier potassium channel activity / Voltage gated Potassium channels / response to light intensity / optic nerve development / neuronal cell body membrane / response to amine / action potential / kinesin binding / calyx of Held / voltage-gated potassium channel activity / axolemma / voltage-gated potassium channel complex / axon terminus / dendrite membrane / potassium ion transmembrane transport / cerebellum development / protein tetramerization / potassium ion transport / protein homooligomerization / response to toxic substance / cellular response to xenobiotic stimulus / presynaptic membrane / postsynaptic membrane / transmembrane transporter binding / 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 / 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
Chem-805 / : / Voltage-gated potassium channel KCNC1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsBotte, M. / Huber, S. / Bucher, D. / Klint, J.K. / Rodriguez, D. / Tagmose, L. / Chami, M. / Cheng, R. / Hennig, M. / Abdul Rhaman, W.
Funding support1items
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, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jul 17, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _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 C member 1
B: Potassium voltage-gated channel subfamily C member 1
C: Potassium voltage-gated channel subfamily C member 1
D: Potassium voltage-gated channel subfamily C member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)237,07112
Polymers235,5334
Non-polymers1,5388
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area23010 Å2
ΔGint-202 kcal/mol
Surface area61830 Å2
MethodPISA

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Components

#1: Protein
Potassium voltage-gated channel subfamily C member 1 / NGK2 / Voltage-gated potassium channel subunit Kv3.1 / Voltage-gated potassium channel subunit Kv4


Mass: 58883.180 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNC1 / Production host: Homo sapiens (human) / References: UniProt: P48547
#2: Chemical
ChemComp-805 / 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide


Mass: 345.373 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H15N3O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O
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: Detergent solubilized tetramer of human Kv3.1 potassium ion channel in complex with Lu AG00563
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 219839 / Symmetry type: POINT

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