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- EMDB-9780: Molecular basis for pore blockade of human Sodium channel Nav1.2 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-9780
TitleMolecular basis for pore blockade of human Sodium channel Nav1.2 by mu-conotoxin KIIIA
Map dataThe map after postprocessing in RELION2.1.
Sample
  • Complex: Nav1.2-beta2-KIIIA
    • Complex: Nav1.2-beta2
    • Complex: KIIIA
    • Protein or peptide: Human Voltage gated sodium channel sub-type 1.2
  • Protein or peptide: Sodium channel protein type 2 subunit alpha
  • Protein or peptide: Mu-conotoxin KIIIA
Function / homology
Function and homology information


response to pyrethroid / 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 / intrinsic apoptotic signaling pathway in response to osmotic stress / regulation of atrial cardiac muscle cell membrane depolarization / nerve development / paranode region of axon / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / dentate gyrus development ...response to pyrethroid / 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 / intrinsic apoptotic signaling pathway in response to osmotic stress / regulation of atrial cardiac muscle cell membrane depolarization / nerve development / paranode region of axon / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / dentate gyrus development / node of Ranvier / membrane depolarization during action potential / voltage-gated sodium channel complex / cardiac muscle cell action potential involved in contraction / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / intercalated disc / neuronal action potential / sodium channel regulator activity / sodium ion transmembrane transport / cardiac muscle contraction / T-tubule / myelination / determination of adult lifespan / memory / Sensory perception of sweet, bitter, and umami (glutamate) taste / presynaptic membrane / nervous system development / gene expression / cellular response to hypoxia / response to heat / toxin activity / chemical synaptic transmission / neuron apoptotic process / calmodulin binding / axon / glutamatergic synapse / synapse / extracellular region / membrane / plasma membrane
Similarity search - Function
Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site ...Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site / IQ motif profile. / Voltage-dependent channel domain superfamily / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Ion transport domain / Ion transport protein / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Sodium channel regulatory subunit beta-2 / Mu-conotoxin KIIIB / Sodium channel protein type 2 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human) / Conus kinoshitai (invertebrata)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsPan X / Li Z / Huang X / Huang G / Shen H / Lei J / Yan N
CitationJournal: Science / Year: 2019
Title: Molecular basis for pore blockade of human Na channel Na1.2 by the μ-conotoxin KIIIA.
Authors: Xiaojing Pan / Zhangqiang Li / Xiaoshuang Huang / Gaoxingyu Huang / Shuai Gao / Huaizong Shen / Lei Liu / Jianlin Lei / Nieng Yan /
Abstract: The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human ...The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit, β2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys at the entrance to the selectivity filter. Many interacting residues are specific to Na1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Na channels.
History
DepositionJan 18, 2019-
Header (metadata) releaseFeb 27, 2019-
Map releaseFeb 27, 2019-
UpdateApr 10, 2019-
Current statusApr 10, 2019Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6j8e
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9780.png

Downloads & links

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Map

FileDownload / File: emd_9780.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe map after postprocessing in RELION2.1.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 240 pix.
= 261.84 Å		1.09 Å/pix.
x 240 pix.
= 261.84 Å		1.09 Å/pix.
x 240 pix.
= 261.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05 / Movie #1: 0.05
Minimum - Maximum-0.13213122 - 0.28682157
Average (Standard dev.)0.0005159385 (±0.00825877)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 261.84 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z261.840261.840261.840
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.1320.2870.001

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Supplemental data

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Sample components

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Entire : Nav1.2-beta2-KIIIA

EntireName: Nav1.2-beta2-KIIIA
Components
  • Complex: Nav1.2-beta2-KIIIA
    • Complex: Nav1.2-beta2
    • Complex: KIIIA
    • Protein or peptide: Human Voltage gated sodium channel sub-type 1.2
  • Protein or peptide: Sodium channel protein type 2 subunit alpha
  • Protein or peptide: Mu-conotoxin KIIIA

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Supramolecule #1: Nav1.2-beta2-KIIIA

SupramoleculeName: Nav1.2-beta2-KIIIA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Ternary complex of Human Nav1.2 with Human Voltage-gated sodium channel auxilliary subunit beta2 and mu-conotoxin KIIIA
Molecular weightExperimental: 252 kDa/nm

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Supramolecule #2: Nav1.2-beta2

SupramoleculeName: Nav1.2-beta2 / type: complex / ID: 2 / Parent: 1
Details: Human Nav1.2 with Human Voltage-gated sodium channel auxilliary subunit beta2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: KIIIA

SupramoleculeName: KIIIA / type: complex / ID: 3 / Parent: 1 / Details: mu-conotoxin KIIIA
Source (natural)Organism: Conus kinoshitai (invertebrata)

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Macromolecule #1: Human Voltage gated sodium channel sub-type 1.2

MacromoleculeName: Human Voltage gated sodium channel sub-type 1.2 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGT MAQSVL VPPGPDSFRF FTRESLAAIE QRIAEEKAKR PKQERKDEDD ENGPKPNSDL EAGK SLPFI YGDIPPEMVS VPLEDLDPYY INKKTFIVLN KGKAISRFSA TPALYILTPF NPIRK LAIK ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGT MAQSVL VPPGPDSFRF FTRESLAAIE QRIAEEKAKR PKQERKDEDD ENGPKPNSDL EAGK SLPFI YGDIPPEMVS VPLEDLDPYY INKKTFIVLN KGKAISRFSA TPALYILTPF NPIRK LAIK ILVHSLFNML IMCTILTNCV FMTMSNPPDW TKNVEYTFTG IYTFESLIKI LARGFC LED FTFLRDPWNW LDFTVITFAY VTEFVDLGNV SALRTFRVLR ALKTISVIPG LKTIVGA LI QSVKKLSDVM ILTVFCLSVF ALIGLQLFMG NLRNKCLQWP PDNSSFEINI TSFFNNSL D GNGTTFNRTV SIFNWDEYIE DKSHFYFLEG QNDALLCGNS SDAGQCPEGY ICVKAGRNP NYGYTSFDTF SWAFLSLFRL MTQDFWENLY QLTLRAAGKT YMIFFVLVIF LGSFYLINLI LAVVAMAYE EQNQATLEEA EQKEAEFQQM LEQLKKQQEE AQAAAAAASA ESRDFSGAGG I GVFSESSS VASKLSSKSE KELKNRRKKK KQKEQSGEEE KNDRVRKSES EDSIRRKGFR FS LEGSRLT YEKRFSSPHQ SLLSIRGSLF SPRRNSRASL FSFRGRAKDI GSENDFADDE HST FEDNDS RRDSLFVPHR HGERRHSNVS QASRASRVLP ILPMNGKMHS AVDCNGVVSL VGGP STLTS AGQLLPEGTT TETEIRKRRS SSYHVSMDLL EDPTSRQRAM SIASILTNTM EELEE SRQK CPPCWYKFAN MCLIWDCCKP WLKVKHLVNL VVMDPFVDLA ITICIVLNTL FMAMEH YPM TEQFSSVLSV GNLVFTGIFT AEMFLKIIAM DPYYYFQEGW NIFDGFIVSL SLMELGL AN VEGLSVLRSF RLLRVFKLAK SWPTLNMLIK IIGNSVGALG NLTLVLAIIV FIFAVVGM Q LFGKSYKECV CKISNDCELP RWHMHDFFHS FLIVFRVLCG EWIETMWDCM EVAGQTMCL TVFMMVMVIG NLVVLNLFLA LLLSSFSSDN LAATDDDNEM NNLQIAVGRM QKGIDFVKRK IREFIQKAF VRKQKALDEI KPLEDLNNKK DSCISNHTTI EIGKDLNYLK DGNGTTSGIG S SVEKYVVD ESDYMSFINN PSLTVTVPIA VGESDFENLN TEEFSSESDM EESKEKLNAT SS SEGSTVD IGAPAEGEQP EVEPEESLEP EACFTEDCVR KFKCCQISIE EGKGKLWWNL RKT CYKIVE HNWFETFIVF MILLSSGALA FEDIYIEQRK TIKTMLEYAD KVFTYIFILE MLLK WVAYG FQVYFTNAWC WLDFLIVDVS LVSLTANALG YSELGAIKSL RTLRALRPLR ALSRF EGMR VVVNALLGAI PSIMNVLLVC LIFWLIFSIM GVNLFAGKFY HCINYTTGEM FDVSVV NNY SECKALIESN QTARWKNVKV NFDNVGLGYL SLLQVATFKG WMDIMYAAVD SRNVELQ PK YEDNLYMYLY FVIFIIFGSF FTLNLFIGVI IDNFNQQKKK FGGQDIFMTE EQKKYYNA M KKLGSKKPQK PIPRPANKFQ GMVFDFVTKQ VFDISIMILI CLNMVTMMVE TDDQSQEMT NILYWINLVF IVLFTGECVL KLISLRYYYF TIGWNIFDFV VVILSIVGMF LAELIEKYFV SPTLFRVIR LARIGRILRL IKGAKGIRTL LFALMMSLPA LFNIGLLLFL VMFIYAIFGM S NFAYVKRE VGIDDMFNFE TFGNSMICLF QITTSAGWDG LLAPILNSGP PDCDPDKDHP GS SVKGDCG NPSVGIFFFV SYIIISFLVV VNMYIAVILE NFSVATEESA EPLSEDDFEM FYE VWEKFD PDATQFIEFA KLSDFADALD PPLLIAKPNK VQLIAMDLPM VSGDRIHCLD ILFA FTKRV LGESGEMDAL RIQMEERFMA SNPSKVSYEP ITTTLKRKQE EVSAIIIQRA YRRYL LKQK VKKVSSIYKK DKGKECDGTP IKEDTLIDKL NENSTPEKTD MTPSTTSPPS YDSVTK PEK EKFEKDKSEK EDKGKDIRES KK

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Macromolecule #2: Sodium channel protein type 2 subunit alpha

MacromoleculeName: Sodium channel protein type 2 subunit alpha / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString:
GRSMEVTVPA TLNVLNGSDA RLPCTFNSCY TVNHKQFSLN WTYQECNNCS EEMFLQFRMK IINLKLERFQ DRVEFSGNPS KYDVSVMLR NVQPEDEGIY NCYIMNPPDR HRGHGKIHLQ VLM

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Macromolecule #3: Mu-conotoxin KIIIA

MacromoleculeName: Mu-conotoxin KIIIA / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Conus kinoshitai (invertebrata)
SequenceString:
CCNCSSKWCR DHSRCC

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 5.9
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 200275
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-6j8e:
Human Nav1.2-beta2-KIIIA ternary complex

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