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Open data
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Basic information
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Title | cryo-EM structure of human NaV1.3/beta1/beta2-bulleyaconitineA | |||||||||
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Function / homology | ![]() 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 / 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 / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction ...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 / 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 / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / voltage-gated monoatomic ion channel activity / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / membrane depolarization during action potential / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / voltage-gated sodium channel complex / sodium channel inhibitor activity / regulation of monoatomic ion transmembrane transport / locomotion / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / membrane depolarization / intercalated disc / sarcoplasm / neuronal action potential / sodium ion transmembrane transport / sodium channel regulator activity / cardiac muscle contraction / T-tubule / axon guidance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / nervous system development / gene expression / response to heat / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / axon / synapse / extracellular region / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
![]() | Jiang D / Li X | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 59.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.3 KB 15.3 KB | Display Display | ![]() |
Images | ![]() | 108.2 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7w77MC ![]() 7w7fC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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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: 1.04 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : Sodium channel complex of type 3 subunit alpha with auxiliary sub...
Entire | Name: Sodium channel complex of type 3 subunit alpha with auxiliary subunits bata-1 and bata-2 |
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Components |
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-Supramolecule #1: Sodium channel complex of type 3 subunit alpha with auxiliary sub...
Supramolecule | Name: Sodium channel complex of type 3 subunit alpha with auxiliary subunits bata-1 and bata-2 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-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: ![]() |
Molecular weight | Theoretical: 24.732115 KDa |
Recombinant expression | Organism: ![]() |
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 subunit beta-2
Macromolecule | Name: Sodium channel subunit beta-2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 24.355859 KDa |
Recombinant expression | Organism: ![]() |
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 #3: Sodium channel protein type 3 subunit alpha
Macromolecule | Name: Sodium channel protein type 3 subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 221.036625 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 DKLNG |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #7: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...
Macromolecule | Name: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en type: ligand / ID: 7 / Number of copies: 3 / Formula: 9Z9 |
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Molecular weight | Theoretical: 544.805 Da |
Chemical component information | ![]() ChemComp-9Z9: |
-Macromolecule #8: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...
Macromolecule | Name: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate type: ligand / ID: 8 / Number of copies: 16 / Formula: 6OU |
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Molecular weight | Theoretical: 717.996 Da |
Chemical component information | ![]() ChemComp-6OU: |
-Macromolecule #9: [(1S,2R,3R,4R,5R,6S,8R,9S,13S,16S,17R,18R)-11-ethyl-5-hydroxy-6,1...
Macromolecule | Name: [(1S,2R,3R,4R,5R,6S,8R,9S,13S,16S,17R,18R)-11-ethyl-5-hydroxy-6,16,18-trimethoxy-4-(4-methoxybenzoyl)-13-(methoxymethyl)-11-azahexacyclo[7.7.2.12,5.01,10.03,8.013,17]nonadecan-8-yl] acetate type: ligand / ID: 9 / Number of copies: 1 / Formula: 966 |
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Molecular weight | Theoretical: 627.765 Da |
Chemical component information | ![]() ChemComp-966: |
-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: 7.5 |
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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 K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 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
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1403849 |
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Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |