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- PDB-9l8w: Human KCNQ2-CaM in complex with QO-58 -

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Basic information

Entry
Database: PDB / ID: 9l8w
TitleHuman KCNQ2-CaM in complex with QO-58
ComponentsPotassium voltage-gated channel subfamily KQT member 2
KeywordsMEMBRANE PROTEIN / KCNQ2
Function / homology
Function and homology information


axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / voltage-gated monoatomic cation channel activity / ankyrin binding / action potential / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / voltage-gated monoatomic cation channel activity / ankyrin binding / action potential / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / nervous system development / chemical synaptic transmission / calmodulin binding / synapse / membrane / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsZhao, Y.W. / Yang, Z.N. / Du, X.N. / Guo, J.T.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)U21A20359 China
CitationJournal: Cell Rep / Year: 2025
Title: Structure basis for the activation of KCNQ2 by endogenous and exogenous ligands.
Authors: Yiwen Zhao / Zhenni Yang / Sai Shi / Han Hao / Xinmeng Li / Demin Ma / Nannan Su / Weixin Zhao / Jicheng Shao / Yating An / Ke Wang / Yinuo Liu / Lu Zou / Jinlong Qi / Hailin Zhang / Jiangtao Guo / Xiaona Du /
Abstract: The voltage-gated potassium channel KCNQ2 is crucial for stabilizing neuronal membrane potential, and its mutations can cause various epilepsies. KCNQ2 is activated by endogenous ligand ...The voltage-gated potassium channel KCNQ2 is crucial for stabilizing neuronal membrane potential, and its mutations can cause various epilepsies. KCNQ2 is activated by endogenous ligand phosphatidylinositol-4,5-bisphosphate (PIP) and exogenous ligands, yet the structural mechanisms underlying these activations remain unclear. Here, we report the cryo-electron microscopy structures of human KCNQ2 in complex with exogenous ligands QO-58 and QO-83 in the absence or presence of PIP in either closed or open conformation. While QO-83 binds in the classical fenestration pocket of the pore domain, QO-58 mainly binds at the flank of S4 in the voltage-sensing domain. These structures, along with electrophysiological assays and computational studies, provide mechanistic insights into the ligand activation of KCNQ2 and may guide the development of anti-epileptic drugs targeting KCNQ2.
History
DepositionDec 28, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 2
B: Potassium voltage-gated channel subfamily KQT member 2
C: Potassium voltage-gated channel subfamily KQT member 2
D: Potassium voltage-gated channel subfamily KQT member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)387,45212
Polymers383,9074
Non-polymers3,5458
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Potassium voltage-gated channel subfamily KQT member 2 / KQT-like 2 / Neuroblastoma-specific potassium channel subunit alpha KvLQT2 / Voltage-gated ...KQT-like 2 / Neuroblastoma-specific potassium channel subunit alpha KvLQT2 / Voltage-gated potassium channel subunit Kv7.2


Mass: 95976.742 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: O43526
#2: Chemical
ChemComp-A1LVR / QO-58 / 5-[2,6-bis(chloranyl)-5-fluoranyl-pyridin-3-yl]-3-phenyl-2-(trifluoromethyl)-4~{H}-pyrazolo[1,5-a]pyrimidin-7-one


Mass: 443.182 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C18H8Cl2F4N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: Human KCNQ2-CaM in complex with QO-58 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 103232 / Symmetry type: POINT

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