Target Information

General Information of This Target
Target ID
BTDT00040
Target Name
Sodium channel protein type 3 subunit alpha (Scn3a)
Target Bioclass
Transporter and channel
Uniprot ID
P08104
3D Structure
Download
2D Sequence
3D Structure
Source
Predict by Alphafold2
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Alphafold Parameters: msa_mode: mmseqs2_uniref_env model_type: auto num_recycles: auto
Gene Name
Scn3a
Gene ID
497770
Synonym
Sodium channel protein brain III subunit alpha; Sodium channel protein type III subunit alpha; Voltage-gated sodium channel subtype III; Voltage-gated sodium channel subunit alpha Nav1.3
Sequence
MAQALLVPPGPESFRLFTRESLAAIEKRAAEEKAKKPKKEQDIDDENKPKPNSDLEAGKN
LPFIYGDIPPEMVSEPLEDLDPYYVSKKTFVVLNKGKAIFRFSATSALYILTPLNPVRKI
AIKILVHSLFSMLIMCTILTNCVFMTLSNPPDWTKNVEYTFTGIYTFESLIKILARGFCL
EDFTFLRDPWNWLDFSVIVMAYVTEFVDLGNVSALRTFRVLRALKTISVIPGLKTIVGAL
IQSVKKLSDVMILTVFCLSVFALIGLQLFMGNLRNKCSQWPPSDSAFETNTTSYFNGTMD
SNGTFVNVTMSTFNWKDYIADDSHFYVLDGQKDPLLCGNGSDAGQCPEGYICVKAGRNPN
YGYTSFDTFSWAFLSLFRLMTQDYWENLYQLTLRAAGKTYMIFFVLVIFLGSFYLVNLIL
AVVAMAYEEQNQATLEEAEQKEAEFQQMLEQLKKQQEEAQAVAAASAASRDFSGIGGLGE
LLESSSEASKLSSKSAKEWRNRRKKRRQREHLEGNHRADGDRFPKSESEDSVKRRSFLLS
LDGNPLTGDKKLCSPHQSLLSIRGSLFSPRRNSKTSIFSFRGRAKDVGSENDFADDEHST
FEDSESRRDSLFVPHRPGERRNSNGTTTETEVRKRRLSSYQISMEMLEDSSGRQRSMSIA
SILTNTMEELEESRQKCPPCWYRFANVFLIWDCCDAWLKVKHLVNLIVMDPFVDLAITIC
IVLNTLFMAMEHYPMTQQFSSVLTVGNLVFTGIFTAEMVLKIIAMDPYYYFQEGWNIFDG
IIVSLSLMELGLANVEGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVL
AIIVFIFAVVGMQLFGKSYKECVCKINVDCKLPRWHMNDFFHSFLIVFRVLCGEWIETMW
DCMEVAGQTMCLIVFMLVMVIGNLVVLNLFLALLLSSFSSDNLAATDDDNEMNNLQIAVG
RMQKGIDFVKNKIRECFRKAFFRKPKVIEIQEGNKIDSCMSNNTGIEISKELNYLKDGNG
TTSGVGTGSSVEKYVIDENDYMSFINNPSLTVTVPIAVGESDFENLNTEEFSSESELEES
KEKLNATSSSEGSTVDVAPPREGEQAEIEPEEDLKPEACFTEGCIKKFPFCQVSTEEGKG
KIWWNLRKTCYSIVEHNWFETFIVFMILLSSGALAFEDIYIEQRKTIKTMLEYADKVFTY
IFILEMLLKWVAYGFQTYFTNAWCWLDFLIVDVSLVSLVANALGYSELGAIKSLRTLRAL
RPLRALSRFEGMRVVVNALVGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYHCVNTTT
GNMFEIKEVNNFSDCQALGKQARWKNVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDS
RDVKLQPIYEENLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKFGGQDIFMTEEQ
KKYYNAMKKLGSKKPQKPIPRPANKFQGMVFDFVTRQVFDISIMILICLNMVTMMVETDD
QSKYMTLVLSRINLVFIVLFTGEFLLKLISLRYYYFTIGWNIFDFVVVILSIVGMFLAEL
IEKYFVSPTLFRVIRLARIGRILRLIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIY
AIFGMSNFAYVKKEAGIDDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSAPPDCDPD
AIHPGSSVKGDCGNPSVGIFFFVSYIIISFLVVVNMYIAVILENFSVATEESAEPLSEDD
FEMFYEVWEKFDPDATQFIEFCKLSDFAAALDPPLLIAKPNKVQLIAMDLPMVSGDRIHC
LDILFAFTKRVLGESGEMDALRIQMEDRFMASNPSKVSYEPITTTLKRKQEEVSAAIIQR
NYRCYLLKQRLKNISSKYDKETIKGRIDLPIKGDMVIDKLNGNSTPEKTDGSSSTTSPPS
YDSVTKPDKEKFEKDKPEKEIKGKEVRENQK

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Family
the sodium channel (TC 1.A.1.10) family
Function
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, forms a sodium- selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. May contribute to the regulation of serotonin/5-hydroxytryptamine release by enterochromaffin cells. In pancreatic endocrine cells, required for both glucagon and glucose-induced insulin secretion.

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Taxonomy ID
10116
TCDB ID
1.A.1.10.1
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Rodentia
Family: Muridae
Genus: Rattus
Species: Rattus norvegicus
Toxin Information Related to This Target
                           Toxin Name Activity Data Type Activity Data Reference
 Toxin Info    Mu-conotoxin BuIIIB Dissociation constant
200 nM
 [1- 5]
 Toxin Info    N.vectensis toxin 4 Effect . [6]
 Toxin Info    N.vectensis toxin 5 Effect . [6]
 Toxin Info    Nemertide alpha-6 Effective concentration 50
24.3 nM
 [7], [8]
 Toxin Info    Nemertide alpha-7 Effective concentration 50
50.4 nM
 [7], [8]
 Toxin Info    Nemertide alpha-2 Effective concentration 50
97.9 nM
 [7], [8]
 Toxin Info    RTX-VII Effective concentration 50
120 nM
 [9]
 Toxin Info    Nemertide alpha-2 Effective concentration 50
127.7 nM
 [7], [8]
 Toxin Info    Nemertide alpha-4 Effective concentration 50
134.2 nM
 [7], [8]
 Toxin Info    Nemertide alpha-1 Effective concentration 50
135.4 nM
 [7], [8], [10]
 Toxin Info    Nemertide alpha-1 Effective concentration 50
135.4 nM
 [7], [8], [10]
 Toxin Info    Nemertide alpha-3 Effective concentration 50
137.8 nM
 [7], [8]
 Toxin Info    Nemertide alpha-3 Effective concentration 50
137.8 nM
 [7], [8]
 Toxin Info    Nemertide alpha-5 Effective concentration 50
156.1 nM
 [7], [8]
 Toxin Info    Beta/kappa-theraphotoxin-Hlv1a IC50
160 nM
 [11]
 Toxin Info    Voltage sensor toxin 3 IC50
210 nM
 [12]
 Toxin Info    Voltage sensor toxin 3 IC50
210 nM
 [13]
 Toxin Info    Huwentoxin-IV IC50
338 nM
 [14- 30]
 Toxin Info    Delta-theraphotoxin-Cg1a 2 IC50
845 nM
 [31- 37]
 Toxin Info    Delta-theraphotoxin-Cg1a 3 IC50
845 nM
 [31- 37]
 Toxin Info    Delta-theraphotoxin-Cg1a 1 IC50
845 nM
 [32- 38]
 Toxin Info    HWTX-IV IC50
˜1.35 μM
 [22]
 Toxin Info    O-MrVIB IC50
1 μM
 [39]
 Toxin Info    ProTx2 IC50
1 μM
 [11]
 Toxin Info    PnCS2 IC50
1.1 ± 0.2 μM
 [40]
 Toxin Info    PnCS4 IC50
2.1 ± 0.6 μM
 [40]
 Toxin Info    Mu-conotoxin PIIIA IC50
3.2 μM
 [1- 47]
 Toxin Info    PnCS3 IC50
5.4 ± 0.1 μM
 [40]
 Toxin Info    PTx2-3258 IC50
14.093 μM
 [48]
 Toxin Info    PTx2-3127 IC50
20.04 μM
 [49]
 Toxin Info    PnCS2 IC50
23 ± 1.6 μM
 [40]
References
Ref 1 Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon. 2009 Jan;53(1):90-8. doi: 10.1016/j.toxicon.2008.10.017. Epub 2008 Nov 20.
Ref 2 Characterization of the Conus bullatus genome and its venom-duct transcriptome. BMC Genomics. 2011 Jan 25;12:60. doi: 10.1186/1471-2164-12-60.
Ref 3 -Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10302-7. doi: 10.1073/pnas.1107027108. Epub 2011 Jun 7.
Ref 4 - and -subunit composition of voltage-gated sodium channels investigated with -conotoxins and the recently discovered O-conotoxin GVIIJ. J Neurophysiol. 2015 Apr 1;113(7):2289-301. doi: 10.1152/jn.01004.2014. Epub 2015 Jan 28.
Ref 5 Mammalian neuronal sodium channel blocker -conotoxin BuIIIB has a structured N-terminus that influences potency. ACS Chem Biol. 2013;8(6):1344-51. doi: 10.1021/cb300674x. Epub 2013 Apr 16.
Ref 6 The Birth and Death of Toxins with Distinct Functions: A Case Study in the Sea Anemone Nematostella. Mol Biol Evol. 2019 Sep 1;36(9):2001-2012. doi: 10.1093/molbev/msz132.
Ref 7 Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Sci Rep. 2018 Mar 22;8(1):4596. doi: 10.1038/s41598-018-22305-w.
Ref 8 Functional Characterization of the Nemertide Family of Peptide Toxins. J Nat Prod. 2021 Aug 27;84(8):2121-2128. doi: 10.1021/acs.jnatprod.1c00104. Epub 2021 Aug 16.
Ref 9 Synergetic action of domain II and IV underlies persistent current generation in Nav1.3 as revealed by a tarantula toxin. Sci Rep. 2015 Mar 18;5:9241. doi: 10.1038/srep09241.
Ref 10 Compound Heterozygous SCN5A Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report. Front Cardiovasc Med. 2020 Jul 24;7:117. doi: 10.3389/fcvm.2020.00117. eCollection 2020.
Ref 11 Novel peptides isolated from spider venom, and uses thereof
Ref 12 Two tarantula venom peptides as potent and differential Na(V) channels blockers. Toxicon. 2014 Jan;77:58-67. doi: 10.1016/j.toxicon.2013.10.029. Epub 2013 Nov 7.
Ref 13 Localization of the voltage-sensor toxin receptor on KvAP. Biochemistry. 2004 Aug 10;43(31):10071-9. doi: 10.1021/bi049463y.
Ref 14 cDNA sequence analysis of seven peptide toxins from the spider Selenocosmia huwena. Toxicon. 2003 Dec;42(7):715-23. doi: 10.1016/j.toxicon.2003.08.007.
Ref 15 Molecular diversification based on analysis of expressed sequence tags from the venom glands of the Chinese bird spider Ornithoctonus huwena. Toxicon. 2008 Jun 15;51(8):1479-89. doi: 10.1016/j.toxicon.2008.03.024. Epub 2008 Mar 27.
Ref 16 Function and solution structure of huwentoxin-IV, a potent neuronal tetrodotoxin (TTX)-sensitive sodium channel antagonist from Chinese bird spider Selenocosmia huwena. J Biol Chem. 2002 Dec 6;277(49):47564-71. doi: 10.1074/jbc.M204063200. Epub 2002 Sep 11.
Ref 17 Native pyroglutamation of huwentoxin-IV: a post-translational modification that increases the trapping ability to the sodium channel. PLoS One. 2013 Jun 24;8(6):e65984. doi: 10.1371/journal.pone.0065984. Print 2013.
Ref 18 Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration. J Biol Chem. 2008 Oct 3;283(40):27300-13. doi: 10.1074/jbc.M708447200. Epub 2008 Jul 14.
Ref 19 Synthesis and characterization of huwentoxin-IV, a neurotoxin inhibiting central neuronal sodium channels. Toxicon. 2008 Feb;51(2):230-9. doi: 10.1016/j.toxicon.2007.09.008. Epub 2007 Sep 29.
Ref 20 The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. Mol Pharmacol. 2010 Dec;78(6):1124-34. doi: 10.1124/mol.110.066332. Epub 2010 Sep 20.
Ref 21 Common molecular determinants of tarantula huwentoxin-IV inhibition of Na+ channel voltage sensors in domains II and IV. J Biol Chem. 2011 Aug 5;286(31):27301-10. doi: 10.1074/jbc.M111.246876. Epub 2011 Jun 9.
Ref 22 Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena. Peptides. 2013 Jun;44:40-6. doi: 10.1016/j.peptides.2013.03.011. Epub 2013 Mar 19.
Ref 23 Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel. J Med Chem. 2015 Mar 12;58(5):2299-314. doi: 10.1021/jm501765v. Epub 2015 Feb 19.
Ref 24 Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes. J Biol Chem. 2018 Jun 8;293(23):9041-9052. doi: 10.1074/jbc.RA118.002553. Epub 2018 Apr 27.
Ref 25 Screening, large-scale production and structure-based classification of cystine-dense peptides. Nat Struct Mol Biol. 2018 Mar;25(3):270-278. doi: 10.1038/s41594-018-0033-9. Epub 2018 Feb 26.
Ref 26 Chemical Synthesis, Proper Folding, Na(v) Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1. Toxins (Basel). 2019 Jun 21;11(6):367. doi: 10.3390/toxins11060367.
Ref 27 Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin huwentoxin-IV (-TRTX-Hh2a). J Biol Chem. 2013 Aug 2;288(31):22707-20. doi: 10.1074/jbc.M113.461392. Epub 2013 Jun 12.
Ref 28 Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNa(V)1.7. Biochim Biophys Acta Biomembr. 2017 May;1859(5):835-844. doi: 10.1016/j.bbamem.2017.01.020. Epub 2017 Jan 20.
Ref 29 The structure, dynamics and selectivity profile of a NaV1.7 potency-optimised huwentoxin-IV variant. PLoS One. 2017 Mar 16;12(3):e0173551. doi: 10.1371/journal.pone.0173551. eCollection 2017.
Ref 30 Structures of human Na(v)1.7 channel in complex with auxiliary subunits and animal toxins. Science. 2019 Mar 22;363(6433):1303-1308. doi: 10.1126/science.aaw2493. Epub 2019 Feb 14.
Ref 31 Molecular diversity and evolution of cystine knot toxins of the tarantula Chilobrachys jingzhao. Cell Mol Life Sci. 2008 Aug;65(15):2431-44. doi: 10.1007/s00018-008-8135-x.
Ref 32 Proteomic and peptidomic analysis of the venom from Chinese tarantula Chilobrachys jingzhao. Proteomics. 2007 Jun;7(11):1892-907. doi: 10.1002/pmic.200600785.
Ref 33 Effects and mechanism of Chinese tarantula toxins on the Kv2.1 potassium channels. Biochem Biophys Res Commun. 2007 Jan 19;352(3):799-804. doi: 10.1016/j.bbrc.2006.11.086. Epub 2006 Nov 27.
Ref 34 Characterization of the excitatory mechanism induced by Jingzhaotoxin-I inhibiting sodium channel inactivation. Toxicon. 2007 Sep 15;50(4):507-17. doi: 10.1016/j.toxicon.2007.04.018. Epub 2007 May 3.
Ref 35 Molecular determinants for the tarantula toxin jingzhaotoxin-I interacting with potassium channel Kv2.1. Toxicon. 2013 Mar 1;63:129-36. doi: 10.1016/j.toxicon.2012.12.001. Epub 2012 Dec 13.
Ref 36 Molecular determinant for the tarantula toxin Jingzhaotoxin-I slowing the fast inactivation of voltage-gated sodium channels. Toxicon. 2016 Mar 1;111:13-21. doi: 10.1016/j.toxicon.2015.12.009. Epub 2015 Dec 23.
Ref 37 Sequence-specific assignment of 1H-NMR resonance and determination of the secondary structure of Jingzhaotoxin-I. Acta Biochim Biophys Sin (Shanghai). 2005 Aug;37(8):567-72. doi: 10.1111/j.1745-7270.2005.00078.x.
Ref 38 Jingzhaotoxin-I, a novel spider neurotoxin preferentially inhibiting cardiac sodium channel inactivation. J Biol Chem. 2005 Apr 1;280(13):12069-76. doi: 10.1074/jbc.M411651200. Epub 2004 Nov 17.
Ref 39 muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):17030-5. doi: 10.1073/pnas.0601819103. Epub 2006 Oct 31.
Ref 40 Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors. FASEB J. 2019 Mar;33(3):3693-3703. doi: 10.1096/fj.201801909R. Epub 2018 Dec 3.
Ref 41 Definition of the M-conotoxin superfamily: characterization of novel peptides from molluscivorous Conus venoms. Biochemistry. 2005 Jun 7;44(22):8176-86. doi: 10.1021/bi047541b.
Ref 42 mu-Conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes. J Neurosci. 1998 Jun 15;18(12):4473-81. doi: 10.1523/JNEUROSCI.18-12-04473.1998.
Ref 43 Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA. J Neurosci. 2000 Jan 1;20(1):76-80. doi: 10.1523/JNEUROSCI.20-01-00076.2000.
Ref 44 A novel -conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors. Br J Pharmacol. 2012 Jul;166(5):1654-68. doi: 10.1111/j.1476-5381.2012.01837.x.
Ref 45 Co-expression of Na(V) subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking -conotoxins. Br J Pharmacol. 2013 Apr;168(7):1597-610. doi: 10.1111/bph.12051.
Ref 46 Structurally diverse -conotoxin PIIIA isomers block sodium channel NaV 1.4. Angew Chem Int Ed Engl. 2012 Apr 23;51(17):4058-61. doi: 10.1002/anie.201107011. Epub 2012 Mar 12.
Ref 47 Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels. J Biol Chem. 2002 Jul 26;277(30):27247-55. doi: 10.1074/jbc.M201611200. Epub 2002 May 2.
Ref 48 The alchemy of culture: intoxicants in society. BMJ. 1998 Nov 28;317(7171):1532B. doi: 10.1136/bmj.317.7171.1532b.
Ref 49 Computational design of peptides to target Na(V)1.7 channel with high potency and selectivity for the treatment of pain. Elife. 2022 Dec 28;11:e81727. doi: 10.7554/eLife.81727.
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