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- EMDB-32343: Cryo-EM structure of human NaV1.3/beta1/beta2-ICA121431 -

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Basic information

Entry
Database: EMDB / ID: EMD-32343
TitleCryo-EM structure of human NaV1.3/beta1/beta2-ICA121431
Map data
Sample
  • Complex: Sodium channel complex of type 3 subunit alpha with auxiliary beta-1 and beta-2
    • Protein or peptide: Sodium channel subunit beta-1
    • Protein or peptide: Sodium channel subunit beta-2
    • Protein or peptide: Sodium channel protein type 3 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: 2,2-diphenyl-~{N}-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]ethanamide
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
Function / homology
Function and homology information


corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / membrane depolarization during action potential / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / membrane depolarization during action potential / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / voltage-gated monoatomic ion channel activity / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / cardiac muscle cell action potential involved in contraction / locomotion / voltage-gated sodium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / regulation of monoatomic ion transmembrane transport / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / sodium ion transport / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / membrane depolarization / neuronal action potential / sarcoplasm / sodium ion transmembrane transport / sodium channel regulator activity / intercalated disc / cardiac muscle contraction / T-tubule / axon guidance / positive regulation of neuron projection development / Sensory perception of sweet, bitter, and umami (glutamate) taste / gene expression / nervous system development / response to heat / perikaryon / chemical synaptic transmission / transmembrane transporter binding / cell adhesion / axon / synapse / extracellular region / plasma membrane
Similarity search - Function
Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / IQ motif profile. ...Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / IQ motif profile. / IQ motif, EF-hand binding site / 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 subunit beta-2 / Sodium channel subunit beta-1 / Sodium channel protein type 3 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsJiang D / Li X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis for modulation of human Na1.3 by clinical drug and selective antagonist.
Authors: Xiaojing Li / Feng Xu / Hao Xu / Shuli Zhang / Yiwei Gao / Hongwei Zhang / Yanli Dong / Yanchun Zheng / Bei Yang / Jianyuan Sun / Xuejun Cai Zhang / Yan Zhao / Daohua Jiang /
Abstract: Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, ...Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na channels and pave a way for subtype-selective therapeutic development.
History
DepositionDec 4, 2021-
Header (metadata) releaseApr 6, 2022-
Map releaseApr 6, 2022-
UpdateApr 6, 2022-
Current statusApr 6, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32343.png

Downloads & links

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Map

FileDownload / File: emd_32343.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 4.05
Minimum - Maximum-17.381546 - 24.053123
Average (Standard dev.)0.0074408436 (±1.5042483)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Sodium channel complex of type 3 subunit alpha with auxiliary bet...

EntireName: Sodium channel complex of type 3 subunit alpha with auxiliary beta-1 and beta-2
Components
  • Complex: Sodium channel complex of type 3 subunit alpha with auxiliary beta-1 and beta-2
    • Protein or peptide: Sodium channel subunit beta-1
    • Protein or peptide: Sodium channel subunit beta-2
    • Protein or peptide: Sodium channel protein type 3 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: 2,2-diphenyl-~{N}-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]ethanamide
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en

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Supramolecule #1: Sodium channel complex of type 3 subunit alpha with auxiliary bet...

SupramoleculeName: Sodium channel complex of type 3 subunit alpha with auxiliary beta-1 and beta-2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Macromolecule #1: Sodium channel subunit beta-1

MacromoleculeName: Sodium channel subunit beta-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.732115 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: Sodium channel subunit beta-2

MacromoleculeName: Sodium channel subunit beta-2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.355859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #3: Sodium channel protein type 3 subunit alpha

MacromoleculeName: Sodium channel protein type 3 subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 226.516453 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQALLVPPG PESFRLFTRE SLAAIEKRAA EEKAKKPKKE QDNDDENKPK PNSDLEAGKN LPFIYGDIPP EMVSEPLEDL DPYYINKKT FIVMNKGKAI FRFSATSALY ILTPLNPVRK IAIKILVHSL FSMLIMCTIL TNCVFMTLSN PPDWTKNVEY T FTGIYTFE ...String:
MAQALLVPPG PESFRLFTRE SLAAIEKRAA EEKAKKPKKE QDNDDENKPK PNSDLEAGKN LPFIYGDIPP EMVSEPLEDL DPYYINKKT FIVMNKGKAI FRFSATSALY ILTPLNPVRK IAIKILVHSL FSMLIMCTIL TNCVFMTLSN PPDWTKNVEY T FTGIYTFE SLIKILARGF CLEDFTFLRD PWNWLDFSVI VMAYVTEFVS LGNVSALRTF RVLRALKTIS VIPGLKTIVG AL IQSVKKL SDVMILTVFC LSVFALIGLQ LFMGNLRNKC LQWPPSDSAF ETNTTSYFNG TMDSNGTFVN VTMSTFNWKD YIG DDSHFY VLDGQKDPLL CGNGSDAGQC PEGYICVKAG RNPNYGYTSF DTFSWAFLSL FRLMTQDYWE NLYQLTLRAA GKTY MIFFV LVIFLGSFYL VNLILAVVAM AYEEQNQATL EEAEQKEAEF QQMLEQLKKQ QEEAQAVAAA SAASRDFSGI GGLGE LLES SSEASKLSSK SAKEWRNRRK KRRQREHLEG NNKGERDSFP KSESEDSVKR SSFLFSMDGN RLTSDKKFCS PHQSLL SIR GSLFSPRRNS KTSIFSFRGR AKDVGSENDF ADDEHSTFED SESRRDSLFV PHRHGERRNS NVSQASMSSR MVPGLPA NG KMHSTVDCNG VVSLVGGPSA LTSPTGQLPP EGTTTETEVR KRRLSSYQIS MEMLEDSSGR QRAVSIASIL TNTMEELE E SRQKCPPCWY RFANVFLIWD CCDAWLKVKH LVNLIVMDPF VDLAITICIV LNTLFMAMEH YPMTEQFSSV LTVGNLVFT GIFTAEMVLK IIAMDPYYYF QEGWNIFDGI IVSLSLMELG LSNVEGLSVL RSFRLLRVFK LAKSWPTLNM LIKIIGNSVG ALGNLTLVL AIIVFIFAVV GMQLFGKSYK ECVCKINDDC TLPRWHMNDF FHSFLIVFRV LCGEWIETMW DCMEVAGQTM C LIVFMLVM VIGNLVVLNL FLALLLSSFS SDNLAATDDD NEMNNLQIAV GRMQKGIDYV KNKMRECFQK AFFRKPKVIE IH EGNKIDS CMSNNTGIEI SKELNYLRDG NGTTSGVGTG SSVEKYVIDE NDYMSFINNP SLTVTVPIAV GESDFENLNT EEF SSESEL EESKEKLNAT SSSEGSTVDV VLPREGEQAE TEPEEDLKPE ACFTEGCIKK FPFCQVSTEE GKGKIWWNLR KTCY SIVEH NWFETFIVFM ILLSSGALAF EDIYIEQRKT IKTMLEYADK VFTYIFILEM LLKWVAYGFQ TYFTNAWCWL DFLIV DVSL VSLVANALGY SELGAIKSLR TLRALRPLRA LSRFEGMRVV VNALVGAIPS IMNVLLVCLI FWLIFSIMGV NLFAGK FYH CVNMTTGNMF DISDVNNLSD CQALGKQARW KNVKVNFDNV GAGYLALLQV ATFKGWMDIM YAAVDSRDVK LQPVYEE NL YMYLYFVIFI IFGSFFTLNL FIGVIIDNFN QQKKKFGGQD IFMTEEQKKY YNAMKKLGSK KPQKPIPRPA NKFQGMVF D FVTRQVFDIS IMILICLNMV TMMVETDDQG KYMTLVLSRI NLVFIVLFTG EFVLKLVSLR HYYFTIGWNI FDFVVVILS IVGMFLAEMI EKYFVSPTLF RVIRLARIGR ILRLIKGAKG IRTLLFALMM SLPALFNIGL LLFLVMFIYA IFGMSNFAYV KKEAGIDDM FNFETFGNSM ICLFQITTSA GWDGLLAPIL NSAPPDCDPD TIHPGSSVKG DCGNPSVGIF FFVSYIIISF L VVVNMYIA VILENFSVAT EESAEPLSED DFEMFYEVWE KFDPDATQFI EFSKLSDFAA ALDPPLLIAK PNKVQLIAMD LP MVSGDRI HCLDILFAFT KRVLGESGEM DALRIQMEDR FMASNPSKVS YEPITTTLKR KQEEVSAAII QRNFRCYLLK QRL KNISSN YNKEAIKGRI DLPIKQDMII DKLNGNSTPE KTDGSSSTTS PPSYDSVTKP DKEKFEKDKP EKESKGKEVR ENQK

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #7: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...

MacromoleculeName: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
type: ligand / ID: 7 / Number of copies: 17 / Formula: 6OU
Molecular weightTheoretical: 717.996 Da
Chemical component information

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

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Macromolecule #8: 2,2-diphenyl-~{N}-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]ethanamide

MacromoleculeName: 2,2-diphenyl-~{N}-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]ethanamide
type: ligand / ID: 8 / Number of copies: 1 / Formula: 8DE
Molecular weightTheoretical: 449.545 Da
Chemical component information

ChemComp-8DE:
2,2-diphenyl-~{N}-[4-(1,3-thiazol-2-ylsulfamoyl)phenyl]ethanamide

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Macromolecule #9: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...

MacromoleculeName: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
type: ligand / ID: 9 / Number of copies: 1 / Formula: 9Z9
Molecular weightTheoretical: 544.805 Da
Chemical component information

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6j8e

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1088844

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