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- PDB-7cr7: human KCNQ2-CaM in complex with retigabine -

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Basic information

Entry
Database: PDB / ID: 7cr7
Titlehuman KCNQ2-CaM in complex with retigabine
Components
  • Calmodulin-3
  • Potassium voltage-gated channel subfamily KQT member 2
KeywordsTRANSPORT PROTEIN / ion channel
Function / homology
Function and homology information


axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / negative regulation of high voltage-gated calcium channel activity / ankyrin binding / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / negative regulation of high voltage-gated calcium channel activity / ankyrin binding / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-threonine phosphorylation / protein phosphatase activator activity / voltage-gated potassium channel activity / positive regulation of cyclic-nucleotide phosphodiesterase activity / positive regulation of phosphoprotein phosphatase activity / adenylate cyclase binding / catalytic complex / detection of calcium ion / negative regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle contraction / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / voltage-gated potassium channel complex / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / regulation of calcium-mediated signaling / positive regulation of protein dephosphorylation / titin binding / positive regulation of protein autophosphorylation / sperm midpiece / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / protein serine/threonine kinase activator activity / regulation of heart rate / sarcomere / positive regulation of peptidyl-threonine phosphorylation / regulation of cytokinesis / spindle microtubule / positive regulation of protein serine/threonine kinase activity / spindle pole / response to calcium ion / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / myelin sheath / nervous system development / chemical synaptic transmission / vesicle / transmembrane transporter binding / calmodulin binding / G protein-coupled receptor signaling pathway / centrosome / synapse / calcium ion binding / protein kinase binding / protein-containing complex / nucleus / plasma membrane / cytoplasm
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 / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site ...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 / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / Ion transport domain / Ion transport protein / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Chem-FBX / Potassium voltage-gated channel subfamily KQT member 2 / Calmodulin-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsLi, X. / Lv, D. / Wang, J. / Ye, S. / Guo, J.
Funding support China, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
National Natural Science Foundation of China (NSFC)31870724 China
CitationJournal: Cell Res / Year: 2021
Title: Molecular basis for ligand activation of the human KCNQ2 channel.
Authors: Xiaoxiao Li / Qiansen Zhang / Peipei Guo / Jie Fu / Lianghe Mei / Dashuai Lv / Jiangqin Wang / Dongwu Lai / Sheng Ye / Huaiyu Yang / Jiangtao Guo /
Abstract: The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper- ...The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper-excitability. A list of synthetic compounds have been developed to directly activate KCNQ2, yet our knowledge of their activation mechanism is limited, due to lack of high-resolution structures. Here, we report cryo-electron microscopy (cryo-EM) structures of the human KCNQ2 determined in apo state and in complex with two activators, ztz240 or retigabine, which activate KCNQ2 through different mechanisms. The activator-bound structures, along with electrophysiology analysis, reveal that ztz240 binds at the voltage-sensing domain and directly stabilizes it at the activated state, whereas retigabine binds at the pore domain and activates the channel by an allosteric modulation. By accurately defining ligand-binding sites, these KCNQ2 structures not only reveal different ligand recognition and activation mechanisms, but also provide a structural basis for drug optimization and design.
History
DepositionAug 12, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 16, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2020Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.2Jan 13, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 2
F: Calmodulin-3
B: Potassium voltage-gated channel subfamily KQT member 2
C: Calmodulin-3
D: Potassium voltage-gated channel subfamily KQT member 2
E: Calmodulin-3
G: Potassium voltage-gated channel subfamily KQT member 2
H: Calmodulin-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)363,13512
Polymers361,9218
Non-polymers1,2134
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area34490 Å2
ΔGint-308 kcal/mol
Surface area102070 Å2

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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: 73627.812 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): HEK297 / Production host: Homo sapiens (human) / References: UniProt: O43526
#2: Protein
Calmodulin-3 /


Mass: 16852.545 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P0DP25
#3: Chemical
ChemComp-FBX / ethyl N-[2-azanyl-4-[(4-fluorophenyl)methylamino]phenyl]carbamate / Retigabine, Ezogabine / Retigabine


Mass: 303.331 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18FN3O2 / Feature type: SUBJECT OF INVESTIGATION
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

Component
IDNameTypeEntity IDParent-IDSource
1voltage-gated potassium channel KCNQ2COMPLEX#1-#20RECOMBINANT
2Potassium voltage-gated channel subfamily KQT member 2COMPLEX#11RECOMBINANT
3Calmodulin-3COMPLEX#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1.556 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 67671 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00516548
ELECTRON MICROSCOPYf_angle_d0.74522372
ELECTRON MICROSCOPYf_dihedral_angle_d8.9789688
ELECTRON MICROSCOPYf_chiral_restr0.0412428
ELECTRON MICROSCOPYf_plane_restr0.0052816

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