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- PDB-8qud: Cryo-EM Structure of Human Kv3.1 in Complex with Modulator AUT5 -

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Basic information

Entry
Database: PDB / ID: 8qud
TitleCryo-EM Structure of Human Kv3.1 in Complex with Modulator AUT5
ComponentsPotassium voltage-gated channel subfamily C member 1
KeywordsMEMBRANE PROTEIN / Modulator / Homotetramer / Voltage-gated potassium channel / Kv3.1 / KCNC1
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 / action potential / neuronal cell body membrane / response to amine / 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
: / 1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE / : / CHOLESTEROL HEMISUCCINATE / Voltage-gated potassium channel KCNC1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsChi, G. / Mckinley, G. / Marsden, B. / Pike, A.C.W. / Ye, M. / Brooke, L.M. / Bakshi, S. / Lakshminarayana, B. / Pilati, N. / Marasco, A. ...Chi, G. / Mckinley, G. / Marsden, B. / Pike, A.C.W. / Ye, M. / Brooke, L.M. / Bakshi, S. / Lakshminarayana, B. / Pilati, N. / Marasco, A. / Gunthorpe, M. / Alvaro, G.S. / Large, C.H. / Williams, E. / Sauer, D.B.
Funding support United Kingdom, Switzerland, 2items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
Innovative Medicines Initiative Switzerland
CitationJournal: Nat Commun / Year: 2024
Title: The binding and mechanism of a positive allosteric modulator of Kv3 channels.
Authors: Qiansheng Liang / Gamma Chi / Leonardo Cirqueira / Lianteng Zhi / Agostino Marasco / Nadia Pilati / Martin J Gunthorpe / Giuseppe Alvaro / Charles H Large / David B Sauer / Werner Treptow / ...Authors: Qiansheng Liang / Gamma Chi / Leonardo Cirqueira / Lianteng Zhi / Agostino Marasco / Nadia Pilati / Martin J Gunthorpe / Giuseppe Alvaro / Charles H Large / David B Sauer / Werner Treptow / Manuel Covarrubias /
Abstract: Small-molecule modulators of diverse voltage-gated K (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their ...Small-molecule modulators of diverse voltage-gated K (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel's tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation.
History
DepositionOct 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release

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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
D: Potassium voltage-gated channel subfamily C member 1
C: Potassium voltage-gated channel subfamily C member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)242,24126
Polymers235,4004
Non-polymers6,84122
Water1,946108
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area33370 Å2
ΔGint-435 kcal/mol
Surface area68600 Å2
MethodPISA

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Components

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Protein , 1 types, 4 molecules ABDC

#1: Protein
Potassium voltage-gated channel subfamily C member 1


Mass: 58850.078 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

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Non-polymers , 6 types, 130 molecules

#2: Chemical
ChemComp-WY0 / (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-yloxypyridin-3-yl)imidazolidine-2,4-dione


Mass: 365.383 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H19N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#5: Chemical
ChemComp-PCF / 1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE


Mass: 734.039 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C40H80NO8P
#6: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: K
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / Source method: isolated from a natural source / Formula: H2O

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Details

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: Homotetramer of Human Kv3.1a with modulator AUT5 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.24 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 17329

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7UCSF Chimeramodel fitting
9Coot0.9.8.1model refinement
10PHENIX1.20.1model refinement
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2975775
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1484211 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model buildingPDB-ID: 7PHI

7phi


Accession code: 7PHI / Source name: PDB / Type: experimental model

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