Target Information

General Information of This Target
Target ID
BTDT00068
Target Name
Potassium voltage-gated channel subfamily A member 4 (KCNA4)
Target Bioclass
Transporter and channel
Uniprot ID
P22459
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
KCNA4
Gene ID
3739
Synonym
KCNA4L; HPCN2; Voltage-gated K(+) channel HuKII; Voltage-gated potassium channel HBK4; Voltage-gated potassium channel HK1; Voltage-gated potassium channel subunit Kv1.4
Sequence
MEVAMVSAESSGCNSHMPYGYAAQARARERERLAHSRAAAAAAVAAATAAVEGSGGSGGG
SHHHHQSRGACTSHDPQSSRGSRRRRRQRSEKKKAHYRQSSFPHCSDLMPSGSEEKILRE
LSEEEEDEEEEEEEEEEGRFYYSEDDHGDECSYTDLLPQDEGGGGYSSVRYSDCCERVVI
NVSGLRFETQMKTLAQFPETLLGDPEKRTQYFDPLRNEYFFDRNRPSFDAILYYYQSGGR
LKRPVNVPFDIFTEEVKFYQLGEEALLKFREDEGFVREEEDRALPENEFKKQIWLLFEYP
ESSSPARGIAIVSVLVILISIVIFCLETLPEFRDDRDLVMALSAGGHGGLLNDTSAPHLE
NSGHTIFNDPFFIVETVCIVWFSFEFVVRCFACPSQALFFKNIMNIIDIVSILPYFITLG
TDLAQQQGGGNGQQQQAMSFAILRIIRLVRVFRIFKLSRHSKGLQILGHTLRASMRELGL
LIFFLFIGVILFSSAVYFAEADEPTTHFQSIPDAFWWAVVTMTTVGYGDMKPITVGGKIV
GSLCAIAGVLTIALPVPVIVSNFNYFYHRETENEEQTQLTQNAVSCPYLPSNLLKKFRSS
TSSSLGDKSEYLEMEEGVKESLCAKEEKCQGKGDDSETDKNNCSNAKAVETDV

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Family
the potassium channel family
Function
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium- selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA4 forms a potassium channel that opens in response to membrane depolarization, followed by rapid spontaneous channel closure. Likewise, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation.

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Taxonomy ID
9606
TCDB ID
1.A.1.2.31
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Toxin Information Related to This Target
                           Toxin Name Activity Data Type Activity Data Reference
 Toxin Info    Potassium channel toxin ShK ([pTyr][AEEA]) Dissociation constant
137 nM
 [1]
 Toxin Info    Potassium channel toxin kappa-KTx 2.5 Dissociation constant
71 μM
 [2]
 Toxin Info    OsK1 (E16K) Inhibition rate . [3]
 Toxin Info    Potassium channel toxin alpha-KTx 23.1 Inhibition rate . [4]
 Toxin Info    Potassium channel toxin ShK ([Ppa][AEEA],M21[Nle]) Inhibition rate . [5]
 Toxin Info    OsK1 (E14A,K18D) Inhibition rate . [6]
 Toxin Info    OsK1 (E15A,K19D) Inhibition rate . [6]
 Toxin Info    Neurotoxin HsTX1 Inhibition rate . [7]
 Toxin Info    Neurotoxin HsTX1 (A14R,C19[Abu],C34[Abu]) Inhibition rate . [8]
 Toxin Info    Beta-theraphotoxin-Gr1a Inhibition rate . [9], [10], [11], [12]
 Toxin Info    Beta-theraphotoxin-Gr1b Inhibition rate . [10], [11], [12]
 Toxin Info    Conorfamide-Sr3 Inhibition rate . [13]
 Toxin Info    Kappa-conotoxin RIIIJ Inhibition rate . [14]
 Toxin Info    Kappa-conotoxin RIIIK Inhibition rate . [14]
 Toxin Info    Kappa-theraphotoxin-Gr2c Inhibition rate . [10- 15]
 Toxin Info    Kunitz-type conkunitzin-S1 Inhibition rate . [16], [17], [18]
 Toxin Info    Kunitz-type serine protease inhibitor homolog dendrotoxin I Inhibition rate . [19]
 Toxin Info    Potassium channel toxin alpha-KTx 2.14 Inhibition rate . [20]
 Toxin Info    Potassium channel toxin alpha-KTx 4.6 Inhibition rate . [21]
 Toxin Info    Potassium channel toxin alpha-KTx 4.8 Inhibition rate . [22]
 Toxin Info    Potassium channel toxin alpha-KTx 24.1 Inhibition rate . [23]
 Toxin Info    Potassium channel toxin alpha-KTx 6.3 Inhibition rate . [8]
 Toxin Info    Potassium channel toxin kappa-KTx 2.9 Inhibition rate . [23]
 Toxin Info    Potassium channel toxin alpha-KTx 23.1 Inhibition rate . [4- 24]
 Toxin Info    Toxin VmKTx1 Inhibition rate . [25]
 Toxin Info    Potassium channel toxin alpha-KTx 3.7 Inhibition rate . [3]
 Toxin Info    Potassium channel toxin alpha-KTx 2.13 Inhibition rate . [26]
 Toxin Info    OsK1 (E16K,K20D) Inhibition rate . [3]
 Toxin Info    OsK1 (E16K,K20D) Inhibition rate . [6]
 Toxin Info    OsK1 (E16K,K20D) Inhibition rate . [3]
 Toxin Info    Kappa-theraphotoxin-Gr3a Inhibition rate . [10- 31]
 Toxin Info    M-theraphotoxin-Gr1a Inhibition rate . [10- 42]
 Toxin Info    Potassium channel toxin gamma-KTx 1.1 Inhibition rate . [43- 54]
 Toxin Info    OsK1 (E16K,K20D) Inhibition rate . [3]
 Toxin Info    [D20]- OsK1 Inhibition rate . [3]
 Toxin Info    Kappa-actitoxin-Ael2e Inhibition rate
66 %
 [55]
 Toxin Info    Potassium channel toxin kappa-KTx 2.5 IC50
71 μM
 [2- 57]
References
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Ref 2 The new kappa-KTx 2.5 from the scorpion Opisthacanthus cayaporum. Peptides. 2011 Jul;32(7):1509-17. doi: 10.1016/j.peptides.2011.05.017. Epub 2011 May 23.
Ref 3 K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochem J. 2005 Jan 1;385(Pt 1):95-104. doi: 10.1042/BJ20041379.
Ref 4 Vm24, a natural immunosuppressive peptide, potently and selectively blocks Kv1.3 potassium channels of human T cells. Mol Pharmacol. 2012 Sep;82(3):372-82. doi: 10.1124/mol.112.078006. Epub 2012 May 23.
Ref 5 Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Mol Pharmacol. 2009 Apr;75(4):762-73. doi: 10.1124/mol.108.052704. Epub 2009 Jan 2.
Ref 6 Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogs with a trimmed N-terminal domain. Mol Pharmacol. 2006 Jan;69(1):354-62. doi: 10.1124/mol.105.017210. Epub 2005 Oct 18.
Ref 7 A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel K(V)1.3. Bioconjug Chem. 2022 Nov 16;33(11):2197-2212. doi: 10.1021/acs.bioconjchem.2c00436. Epub 2022 Nov 4.
Ref 8 The impact of the fourth disulfide bridge in scorpion toxins of the alpha-KTx6 subfamily. Proteins. 2005 Dec 1;61(4):1010-23. doi: 10.1002/prot.20681.
Ref 9 Isolation and characterization of a novel toxin from the venom of the spider Grammostola rosea that blocks sodium channels. Toxicon. 2007 Jul;50(1):65-74. doi: 10.1016/j.toxicon.2007.02.015. Epub 2007 Mar 3.
Ref 10 Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels. J Biol Chem. 2010 Feb 5;285(6):4130-4142. doi: 10.1074/jbc.M109.054718. Epub 2009 Dec 2.
Ref 11 Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell. 2019 Feb 7;176(4):702-715.e14. doi: 10.1016/j.cell.2018.12.018. Epub 2019 Jan 17.
Ref 12 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 13 Studies of Conorfamide-Sr3 on Human Voltage-Gated Kv1 Potassium Channel Subtypes. Mar Drugs. 2020 Aug 13;18(8):425. doi: 10.3390/md18080425.
Ref 14 Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: evaluation of cardioprotective effects of kappaM-conotoxins. J Biol Chem. 2010 May 14;285(20):14882-14889. doi: 10.1074/jbc.M109.068486. Epub 2010 Mar 10.
Ref 15 Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea. Toxicon. 2011 Sep 1;58(3):265-76. doi: 10.1016/j.toxicon.2011.06.006. Epub 2011 Jun 28.
Ref 16 Production of recombinant Conkunitzin-S1 in Escherichia coli. Protein Expr Purif. 2006 Jun;47(2):640-4. doi: 10.1016/j.pep.2006.01.019. Epub 2006 Feb 20.
Ref 17 Conkunitzin-S1 is the first member of a new Kunitz-type neurotoxin family. Structural and functional characterization. J Biol Chem. 2005 Jun 24;280(25):23766-70. doi: 10.1074/jbc.C500064200. Epub 2005 Apr 15.
Ref 18 Structure of conkunitzin-S1, a neurotoxin and Kunitz-fold disulfide variant from cone snail. Acta Crystallogr D Biol Crystallogr. 2006 Sep;62(Pt 9):980-90. doi: 10.1107/S0907444906021123. Epub 2006 Aug 19.
Ref 19 Toxin and subunit specificity of blocking affinity of three peptide toxins for heteromultimeric, voltage-gated potassium channels expressed in Xenopus oocytes. J Pharmacol Exp Ther. 1998 Jun;285(3):1051-60.
Ref 20 A K? channel blocking peptide from the Cuban scorpion Rhopalurus garridoi. Peptides. 2014 Mar;53:42-7. doi: 10.1016/j.peptides.2013.10.010. Epub 2013 Oct 25.
Ref 21 Tst26, a novel peptide blocker of Kv1.2 and Kv1.3 channels from the venom of Tityus stigmurus. Toxicon. 2009 Sep 15;54(4):379-89. doi: 10.1016/j.toxicon.2009.05.023. Epub 2009 Jun 3.
Ref 22 Characterization and Chemical Synthesis of Cm39 (-KTx 4.8): A Scorpion Toxin That Inhibits Voltage-Gated K(+) Channel K(V)1.2 and Small- and Intermediate-Conductance Ca(2+)-Activated K(+) Channels K(Ca)2.2 and K(Ca)3.1. Toxins (Basel). 2023 Jan 5;15(1):41. doi: 10.3390/toxins15010041.
Ref 23 Pi5 and Pi6, two undescribed peptides from the venom of the scorpion Pandinus imperator and their effects on K(+)-channels. Toxicon. 2017 Jul;133:136-144. doi: 10.1016/j.toxicon.2017.05.011. Epub 2017 May 11.
Ref 24 Structure, function, and chemical synthesis of Vaejovis mexicanus peptide 24: a novel potent blocker of Kv1.3 potassium channels of human T lymphocytes. Biochemistry. 2012 May 15;51(19):4049-61. doi: 10.1021/bi300060n. Epub 2012 May 7.
Ref 25 sVmKTx, a transcriptome analysis-based synthetic peptide analogue of Vm24, inhibits Kv1.3 channels of human T cells with improved selectivity. Biochem Pharmacol. 2022 May;199:115023. doi: 10.1016/j.bcp.2022.115023. Epub 2022 Mar 28.
Ref 26 A selective blocker of Kv1.2 and Kv1.3 potassium channels from the venom of the scorpion Centruroides suffusus suffusus. Biochem Pharmacol. 2008 Oct 30;76(9):1142-54. doi: 10.1016/j.bcp.2008.08.018. Epub 2008 Aug 22.
Ref 27 Functional analysis of an archaebacterial voltage-dependent K+ channel. Nature. 2003 Mar 13;422(6928):180-5. doi: 10.1038/nature01473. Epub 2003 Mar 2.
Ref 28 A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom. Nature. 2004 Jul 8;430(6996):232-5. doi: 10.1038/nature02632.
Ref 29 Localization of the voltage-sensor toxin receptor on KvAP. Biochemistry. 2004 Aug 10;43(31):10071-9. doi: 10.1021/bi049463y.
Ref 30 Vstx1, a modifier of Kv channel gating, localizes to the interfacial region of lipid bilayers. Biochemistry. 2006 Oct 3;45(39):11844-55. doi: 10.1021/bi061111z.
Ref 31 Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel. Biochemistry. 2005 Apr 26;44(16):6015-23. doi: 10.1021/bi0477034.
Ref 32 cDNA sequence and in vitro folding of GsMTx4, a specific peptide inhibitor of mechanosensitive channels. Toxicon. 2003 Sep;42(3):263-74. doi: 10.1016/s0041-0101(03)00141-7.
Ref 33 Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J Gen Physiol. 2000 May;115(5):583-98. doi: 10.1085/jgp.115.5.583.
Ref 34 Solution structure of peptide toxins that block mechanosensitive ion channels. J Biol Chem. 2002 Sep 13;277(37):34443-50. doi: 10.1074/jbc.M202715200. Epub 2002 Jun 24.
Ref 35 Tarantula peptide inhibits atrial fibrillation. Nature. 2001 Jan 4;409(6816):35-6. doi: 10.1038/35051165.
Ref 36 Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature. 2004 Jul 8;430(6996):235-40. doi: 10.1038/nature02743.
Ref 37 Lipid membrane interaction and antimicrobial activity of GsMTx-4, an inhibitor of mechanosensitive channel. Biochem Biophys Res Commun. 2006 Feb 10;340(2):633-8. doi: 10.1016/j.bbrc.2005.12.046. Epub 2005 Dec 19.
Ref 38 Effects of tarantula toxin GsMTx4 on the membrane motor of outer hair cells. Neurosci Lett. 2006 Aug 14;404(1-2):213-6. doi: 10.1016/j.neulet.2006.05.059. Epub 2006 Jun 22.
Ref 39 Molecular dynamics simulations of a stretch-activated channel inhibitor GsMTx4 with lipid membranes: two binding modes and effects of lipid structure. Biophys J. 2007 Jun 15;92(12):4233-43. doi: 10.1529/biophysj.106.101071. Epub 2007 Mar 23.
Ref 40 Is lipid bilayer binding a common property of inhibitor cysteine knot ion-channel blockers?. Biophys J. 2007 Aug 15;93(4):L20-2. doi: 10.1529/biophysj.107.112375. Epub 2007 Jun 15.
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Ref 42 Fast desensitization of acetylcholine receptors induced by a spider toxin. Channels (Austin). 2021 Dec;15(1):507-515. doi: 10.1080/19336950.2021.1961459.
Ref 43 A large number of novel Ergtoxin-like genes and ERG K+-channels blocking peptides from scorpions of the genus Centruroides. FEBS Lett. 2002 Dec 4;532(1-2):121-6. doi: 10.1016/s0014-5793(02)03652-9.
Ref 44 A toxin to nervous, cardiac, and endocrine ERG K+ channels isolated from Centruroides noxius scorpion venom. FASEB J. 1999 May;13(8):953-62.
Ref 45 Disulfide bridges of ergtoxin, a member of a new sub-family of peptide blockers of the ether-a-go-go-related K+ channel. FEBS Lett. 2000 Aug 18;479(3):156-7. doi: 10.1016/s0014-5793(00)01891-3.
Ref 46 Mapping the receptor site for ergtoxin, a specific blocker of ERG channels. FEBS Lett. 2002 Jan 2;510(1-2):45-9. doi: 10.1016/s0014-5793(01)03218-5.
Ref 47 Mapping the binding site of a human ether-a-go-go-related gene-specific peptide toxin (ErgTx) to the channel's outer vestibule. J Biol Chem. 2002 May 10;277(19):16403-11. doi: 10.1074/jbc.M200460200. Epub 2002 Feb 25.
Ref 48 Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Lett. 2003 Jul 17;547(1-3):20-6. doi: 10.1016/s0014-5793(03)00662-8.
Ref 49 Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system. Mol Pharmacol. 2006 May;69(5):1673-83. doi: 10.1124/mol.105.019729. Epub 2006 Feb 23.
Ref 50 Mechanism of block of the hERG K+ channel by the scorpion toxin CnErg1. Biophys J. 2007 Jun 1;92(11):3915-29. doi: 10.1529/biophysj.106.101956. Epub 2007 Mar 16.
Ref 51 Recombinant expression of the toxic peptide ErgTx1 and role of Met35 on its stability and function. Peptides. 2011 Mar;32(3):560-7. doi: 10.1016/j.peptides.2010.06.018. Epub 2010 Jun 30.
Ref 52 Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins. Biochem Biophys Res Commun. 2012 Dec 7;429(1-2):111-6. doi: 10.1016/j.bbrc.2012.10.065. Epub 2012 Oct 24.
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Ref 55 APETx4, a Novel Sea Anemone Toxin and a Modulator of the Cancer-Relevant Potassium Channel K(V)10.1. Mar Drugs. 2017 Sep 13;15(9):287. doi: 10.3390/md15090287.
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