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Yorodumi- EMDB-34388: Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-34388 | |||||||||
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Title | Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / axon initial segment / sodium ion binding ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / axon initial segment / sodium ion binding / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / high voltage-gated calcium channel activity / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / peripheral nervous system development / node of Ranvier / cardiac muscle cell action potential involved in contraction / optic nerve development / voltage-gated sodium channel complex / regulation of ventricular cardiac muscle cell membrane repolarization / locomotion / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / parallel fiber to Purkinje cell synapse / voltage-gated sodium channel activity / voltage-gated calcium channel complex / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / membrane depolarization / calcium ion import across plasma membrane / intercalated disc / sodium channel regulator activity / sodium ion transmembrane transport / neuronal action potential / presynaptic active zone membrane / cardiac muscle contraction / T-tubule / myelination / axon guidance / postsynaptic density membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / Z disc / cell junction / nervous system development / gene expression / response to heat / cytoplasmic vesicle / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / axon / glutamatergic synapse / synapse / extracellular region / ATP binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Li Y / Jiang D | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Structure of human Na1.6 channel reveals Na selectivity and pore blockade by 4,9-anhydro-tetrodotoxin. Authors: Yue Li / Tian Yuan / Bo Huang / Feng Zhou / Chao Peng / Xiaojing Li / Yunlong Qiu / Bei Yang / Yan Zhao / Zhuo Huang / Daohua Jiang / Abstract: The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been ...The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na1.6 inhibition by the blocker. The apo-form structure reveals two potential Na binding sites within the selectivity filter, suggesting a possible mechanism for Na selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na1.6 structure, ion conductance, and inhibition. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_34388.map.gz | 59.4 MB | EMDB map data format | |
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Header (meta data) | emd-34388-v30.xml emd-34388.xml | 18.5 KB 18.5 KB | Display Display | EMDB header |
Images | emd_34388.png | 127.3 KB | ||
Others | emd_34388_half_map_1.map.gz emd_34388_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-34388 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34388 | HTTPS FTP |
-Related structure data
Related structure data | 8gz2MC 8gz1C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_34388.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_34388_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34388_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Structure of human voltage-gated sodium channel Nav1.6 in complex...
Entire | Name: Structure of human voltage-gated sodium channel Nav1.6 in complex with auxiliary beta subunits |
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Components |
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-Supramolecule #1: Structure of human voltage-gated sodium channel Nav1.6 in complex...
Supramolecule | Name: Structure of human voltage-gated sodium channel Nav1.6 in complex with auxiliary beta subunits type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Sodium channel subunit beta-1
Macromolecule | Name: Sodium channel subunit beta-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 24.732115 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MGRLLALVVG AALVSSACGG CVEVDSETEA VYGMTFKILC ISCKRRSETN AETFTEWTFR QKGTEEFVKI LRYENEVLQL EEDERFEGR VVWNGSRGTK DLQDLSIFIT NVTYNHSGDY ECHVYRLLFF ENYEHNTSVV KKIHIEVVDK ANRDMASIVS E IMMYVLIV ...String: MGRLLALVVG AALVSSACGG CVEVDSETEA VYGMTFKILC ISCKRRSETN AETFTEWTFR QKGTEEFVKI LRYENEVLQL EEDERFEGR VVWNGSRGTK DLQDLSIFIT NVTYNHSGDY ECHVYRLLFF ENYEHNTSVV KKIHIEVVDK ANRDMASIVS E IMMYVLIV VLTIWLVAEM IYCYKKIAAA TETAAQENAS EYLAITSESK ENCTGVQVAE |
-Macromolecule #2: Sodium channel protein type 8 subunit alpha
Macromolecule | Name: Sodium channel protein type 8 subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 225.520609 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MAARLLAPPG PDSFKPFTPE SLANIERRIA ESKLKKPPKA DGSHREDDED SKPKPNSDLE AGKSLPFIYG DIPQGLVAVP LEDFDPYYL TQKTFVVLNR GKTLFRFSAT PALYILSPFN LIRRIAIKIL IHSVFSMIIM CTILTNCVFM TFSNPPDWSK N VEYTFTGI ...String: MAARLLAPPG PDSFKPFTPE SLANIERRIA ESKLKKPPKA DGSHREDDED SKPKPNSDLE AGKSLPFIYG DIPQGLVAVP LEDFDPYYL TQKTFVVLNR GKTLFRFSAT PALYILSPFN LIRRIAIKIL IHSVFSMIIM CTILTNCVFM TFSNPPDWSK N VEYTFTGI YTFESLVKII ARGFCIDGFT FLRDPWNWLD FSVIMMAYIT EFVNLGNVSA LRTFRVLRAL KTISVIPGLK TI VGALIQS VKKLSDVMIL TVFCLSVFAL IGLQLFMGNL RNKCVVWPIN FNESYLENGT KGFDWEEYIN NKTNFYTVPG MLE PLLCGN SSDAGQCPEG YQCMKAGRNP NYGYTSFDTF SWAFLALFRL MTQDYWENLY QLTLRAAGKT YMIFFVLVIF VGSF YLVNL ILAVVAMAYE EQNQATLEEA EQKEAEFKAM LEQLKKQQEE AQAAAMATSA GTVSEDAIEE EGEEGGGSPR SSSEI SKLS SKSAKERRNR RKKRKQKELS EGEEKGDPEK VFKSESEDGM RRKAFRLPDN RIGRKFSIMN QSLLSIPGSP FLSRHN SKS SIFSFRGPGR FRDPGSENEF ADDEHSTVEE SEGRRDSLFI PIRARERRSS YSGYSGYSQG SRSSRIFPSL RRSVKRN ST VDCNGVVSLI GGPGSHIGGR LLPEATTEVE IKKKGPGSLL VSMDQLASYG RKDRINSIMS VVTNTLVEEL EESQRKCP P CWYKFANTFL IWECHPYWIK LKEIVNLIVM DPFVDLAITI CIVLNTLFMA MEHHPMTPQF EHVLAVGNLV FTGIFTAEM FLKLIAMDPY YYFQEGWNIF DGFIVSLSLM ELSLADVEGL SVLRSFRLLR VFKLAKSWPT LNMLIKIIGN SVGALGNLTL VLAIIVFIF AVVGMQLFGK SYKECVCKIN QDCELPRWHM HDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVFMM V MVIGNLVV LNLFLALLLS SFSADNLAAT DDDGEMNNLQ ISVIRIKKGV AWTKLKVHAF MQAHFKQREA DEVKPLDELY EK KANCIAN HTGADIHRNG DFQKNGNGTT SGIGSSVEKY IIDEDHMSFI NNPNLTVRVP IAVGESDFEN LNTEDVSSES DPE GSKDKL DDTSSSEGST IDIKPEVEEV PVEQPEEYLD PDACFTEGCV QRFKCCQVNI EEGLGKSWWI LRKTCFLIVE HNWF ETFII FMILLSSGAL AFEDIYIEQR KTIRTILEYA DKVFTYIFIL EMLLKWTAYG FVKFFTNAWC WLDFLIVAVS LVSLI ANAL GYSELGAIKS LRTLRALRPL RALSRFEGMR VVVNALVGAI PSIMNVLLVC LIFWLIFSIM GVNLFAGKYH YCFNET SEI RFEIEDVNNK TECEKLMEGN NTEIRWKNVK INFDNVGAGY LALLQVATFK GWMDIMYAAV DSRKPDEQPK YEDNIYM YI YFVIFIIFGS FFTLNLFIGV IIDNFNQQKK KFGGQDIFMT EEQKKYYNAM KKLGSKKPQK PIPRPLNKIQ GIVFDFVT Q QAFDIVIMML ICLNMVTMMV ETDTQSKQME NILYWINLVF VIFFTCECVL KMFALRHYYF TIGWNIFDFV VVILSIVGM FLADIIEKYF VSPTLFRVIR LARIGRILRL IKGAKGIRTL LFALMMSLPA LFNIGLLLFL VMFIFSIFGM SNFAYVKHEA GIDDMFNFE TFGNSMICLF QITTSAGWDG LLLPILNRPP DCSLDKEHPG SGFKGDCGNP SVGIFFFVSY IIISFLIVVN M YIAIILEN FSVATEESAD PLSEDDFETF YEIWEKFDPD ATQFIEYCKL ADFADALEHP LRVPKPNTIE LIAMDLPMVS GD RIHCLDI LFAFTKRVLG DSGELDILRQ QMEERFVASN PSKVSYEPIT TTLRRKQEEV SAVVLQRAYR GHLARRGFIC KKT TSNKLE NGGTHREKKE STPSTASLPS YDSVTKPEKE KQQRAEEGRR ERAKRQKEVR ESKC |
-Macromolecule #3: Sodium channel subunit beta-2
Macromolecule | Name: Sodium channel subunit beta-2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 24.355859 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MHRDAWLPRP AFSLTGLSLF FSLVPPGRSM EVTVPATLNV LNGSDARLPC TFNSCYTVNH KQFSLNWTYQ ECNNCSEEMF LQFRMKIIN LKLERFQDRV EFSGNPSKYD VSVMLRNVQP EDEGIYNCYI MNPPDRHRGH GKIHLQVLME EPPERDSTVA V IVGASVGG ...String: MHRDAWLPRP AFSLTGLSLF FSLVPPGRSM EVTVPATLNV LNGSDARLPC TFNSCYTVNH KQFSLNWTYQ ECNNCSEEMF LQFRMKIIN LKLERFQDRV EFSGNPSKYD VSVMLRNVQP EDEGIYNCYI MNPPDRHRGH GKIHLQVLME EPPERDSTVA V IVGASVGG FLAVVILVLM VVKCVRRKKE QKLSTDDLKT EEEGKTDGEG NPDDGAK |
-Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #6: (1R,2S,3S,4R,5R,9S,11S,12S,14R)-7-amino-2,4,12-trihydroxy-2-(hydr...
Macromolecule | Name: (1R,2S,3S,4R,5R,9S,11S,12S,14R)-7-amino-2,4,12-trihydroxy-2-(hydroxymethyl)-10,13,15-trioxa-6,8-diazapentacyclo[7.4.1.1~3,12~.0~5,11~.0~5,14~]pentadec-7-en-8-ium (non-preferred name) type: ligand / ID: 6 / Number of copies: 1 / Formula: WMK |
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Molecular weight | Theoretical: 301.253 Da |
Chemical component information | ChemComp-WMK: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 9.2 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 76448 |