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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-30246 | |||||||||
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Title | Cryo-EM structure of human KCNQ4 with linopirdine | |||||||||
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![]() | KCNQ / Channel / Calmodulin / PIP2 / linopirdine / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() Voltage gated Potassium channels / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / negative regulation of high voltage-gated calcium channel activity / inner ear morphogenesis / positive regulation of cyclic-nucleotide phosphodiesterase activity / 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 ...Voltage gated Potassium channels / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / negative regulation of high voltage-gated calcium channel activity / inner ear morphogenesis / positive regulation of cyclic-nucleotide phosphodiesterase activity / 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 / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / voltage-gated potassium channel activity / : / adenylate cyclase binding / potassium channel activity / catalytic complex / detection of calcium ion / regulation of cardiac muscle contraction / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / : / titin binding / regulation of calcium-mediated signaling / positive regulation of protein autophosphorylation / voltage-gated potassium channel complex / sperm midpiece / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / regulation of heart rate / sarcomere / bioluminescence / protein serine/threonine kinase activator activity / basal plasma membrane / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / generation of precursor metabolites and energy / spindle microtubule / sensory perception of sound / potassium ion transport / 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 / vesicle / transmembrane transporter binding / G protein-coupled receptor signaling pathway / centrosome / calcium ion binding / protein kinase binding / protein-containing complex / nucleus / plasma membrane / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
![]() | Shen H / Li T | |||||||||
![]() | ![]() Title: Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs. Authors: Tian Li / Kun Wu / Zhenlei Yue / Yifei Wang / Fan Zhang / Huaizong Shen / ![]() Abstract: Among the five KCNQ channels, also known as the K7 voltage-gated potassium (K) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological ...Among the five KCNQ channels, also known as the K7 voltage-gated potassium (K) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 Å, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 115.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.8 KB 13.8 KB | Display Display | ![]() |
Images | ![]() | 100.9 KB | ||
Filedesc metadata | ![]() | 5.9 KB | ||
Others | ![]() | 115.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7bynMC ![]() 7bylC ![]() 7bymC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.087 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: #1
File | emd_30246_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Complex of human KCNQ4 and linopirdine
Entire | Name: Complex of human KCNQ4 and linopirdine |
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Components |
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-Supramolecule #1: Complex of human KCNQ4 and linopirdine
Supramolecule | Name: Complex of human KCNQ4 and linopirdine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Green fluorescent protein,Potassium voltage-gated channel subfami...
Macromolecule | Name: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 109.327836 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MHHHHHHHHA ADYKDHDIDY KDDDDKSAMV SKGEELFTGV VPILVELDGD VNGHKFSVSG EGEGDATYGK LTLKFICTTG KLPVPWPTL VTTLTYGVQC FSRYPDHMKQ HDFFKSAMPE GYVQERTIFF KDDGNYTTRA EVKFEGDTLV NRIELKGIDF K EDGNILGH ...String: MHHHHHHHHA ADYKDHDIDY KDDDDKSAMV SKGEELFTGV VPILVELDGD VNGHKFSVSG EGEGDATYGK LTLKFICTTG KLPVPWPTL VTTLTYGVQC FSRYPDHMKQ HDFFKSAMPE GYVQERTIFF KDDGNYTTRA EVKFEGDTLV NRIELKGIDF K EDGNILGH KLEYNYNSHN VYIMADKQKN GIKVNFKIRH NIEDGSVQLA DHYQQNTPIG DGPVLLPDNH YLSTQSKLSK DP NEKRDHM VLLEFVTAAG ITLGMDELYK SGLRSGLEVL FQGPGGRMAE APPRRLGLGP PPGDAPRAEL VALTAVQSEQ GEA GGGGSP RRLGLLGSPL PPGAPLPGPG SGSGSACGQR SSAAHKRYRR LQNWVYNVLE RPRGWAFVYH VFIFLLVFSC LVLS VLSTI QEHQELANEC LLILEFVMIV VFGLEYIVRV WSAGCCCRYR GWQGRFRFAR KPFCVIDFIV FVASVAVIAA GTQGN IFAT SALRSMRFLQ ILRMVRMDRR GGTWKLLGSV VYAHSKELIT AWYIGFLVLI FASFLVYLAE KDANSDFSSY ADSLWW GTI TLTTIGYGDK TPHTWLGRVL AAGFALLGIS FFALPAGILG SGFALKVQEQ HRQKHFEKRR MPAANLIQAA WRLYSTD MS RAYLTATWYY YDSILPSFRE LALLFEHVQR ARNGGLRPLE VRRAPVPDGA PSRYPPVATC HRPGSTSFCP GESSRMGI K DRIRMGSSQR RTGPSKQHLA PPTMPTSPSS EQVGEATSPT KVQKSWSFND RTRFRASLRL KPRTSAEDAP SEEVAEEKS YQCELTVDDI MPAVKTVIRS IRILKFLVAK RKFKETLRPY DVKDVIEQYS AGHLDMLGRI KSLQTRVDQI VGRGPGDRKA REKGDKGPS DAEVVDEISM MGRVVKVEKQ VQSIEHKLDL LLGFYSRCLR SGTSASLGAV QVPLFDPDIT SDYHSPVDHE D ISVSAQTL SISRSVSTNM D UniProtKB: Green fluorescent protein, Potassium voltage-gated channel subfamily KQT member 4 |
-Macromolecule #2: Calmodulin-3
Macromolecule | Name: Calmodulin-3 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 16.852545 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK UniProtKB: Calmodulin-3 |
-Macromolecule #3: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tr...
Macromolecule | Name: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate type: ligand / ID: 3 / Number of copies: 4 / Formula: PT5 |
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Molecular weight | Theoretical: 1.047088 KDa |
-Macromolecule #4: POTASSIUM ION
Macromolecule | Name: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: K |
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Molecular weight | Theoretical: 39.098 Da |
-Macromolecule #5: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one
Macromolecule | Name: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one / type: ligand / ID: 5 / Number of copies: 1 / Formula: FCC |
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Molecular weight | Theoretical: 391.464 Da |
Chemical component information | ![]() ChemComp-FCC: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: EMDB MAP |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 229040 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |