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Solution structure of hpTX2, a toxin from Heteropoda venatoria spider that blocks Kv4.2 potassium channel.

Bernard C, Legros C, Ferrat G, Bischoff U, Marquardt A, Pongs O, Darbon H
Protein Sci 9 2059-67 (2000)
Cited: 31 times
EuropePMC logo PMID: 11152117

Abstract

HpTX2 is a toxin from the venom of Heteropoda venatoria spider that has been demonstrated to bind on Kv4.2 potassium channel. We have determined the solution structure of recombinant HpTX2 by use of conventional two-dimensional NMR techniques followed by distance-geometry and molecular dynamics. The calculated structure belongs to the Inhibitory Cystin Knot structural family that consists in a compact disulfide-bonded core, from which four loops emerge. A poorly defined two-stranded antiparallel beta-sheet (residues 20-23 and 25-28) is detected. Analysis of the electrostatic charge anisotropy allows us to propose a functional map of HpTX2 different from the one described for kappa-conotoxin PVIIA, but strongly related to the one of charybdotoxin. The orientation of the dipole moment of HpTX2 emerges through K27 which could therefore be the critical lysine residue. Close to this lysine are a second basic residue, R23, an aromatic cluster (F7, W25, W30) and an hydrophobic side chain (L24). The high density in aromatic side chains of the putative functional surface as well as the lack of an asparagine is proposed to be the structural basis of the specificity of HpTX2 toward Kv4.2 channel.

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Reviews citing this publication (6)

  1. Transient outward potassium current, 'Ito', phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms. Patel SP, Campbell DL. J Physiol 569 7-39 (2005)
  2. Tarantula toxins interacting with voltage sensors in potassium channels. Swartz KJ. Toxicon 49 213-230 (2007)
  3. Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs. Estrada G, Villegas E, Corzo G. Nat Prod Rep 24 145-161 (2007)
  4. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. Toxicon 49 194-201 (2007)
  5. Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel. Nicholson GM, Little MJ, Birinyi-Strachan LC. Toxicon 43 587-599 (2004)
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  1. Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies. Escoubas P, Diochot S, Célérier ML, Nakajima T, Lazdunski M. Mol Pharmacol 62 48-57 (2002)
  2. Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels. Escoubas P, Bernard C, Lambeau G, Lazdunski M, Darbon H. Protein Sci 12 1332-1343 (2003)
  3. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. Smith JJ, Cummins TR, Alphy S, Blumenthal KM. J Biol Chem 282 12687-12697 (2007)
  4. Molecular identification of Kvalpha subunits that contribute to the oxygen-sensitive K+ current of chemoreceptor cells of the rabbit carotid body. Sanchez D, López-López JR, Pérez-García MT, Sanz-Alfayate G, Obeso A, Ganfornina MD, Gonzalez C. J Physiol 542 369-382 (2002)
  5. An unusual fold for potassium channel blockers: NMR structure of three toxins from the scorpion Opisthacanthus madagascariensis. Chagot B, Pimentel C, Dai L, Pil J, Tytgat J, Nakajima T, Corzo G, Darbon H, Ferrat G. Biochem J 388 263-271 (2005)
  6. Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels. Chagot B, Escoubas P, Diochot S, Bernard C, Lazdunski M, Darbon H. Protein Sci 14 2003-2010 (2005)
  7. Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus. Chagot B, Escoubas P, Villegas E, Bernard C, Ferrat G, Corzo G, Lazdunski M, Darbon H. Protein Sci 13 1197-1208 (2004)
  8. Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family. Zarayskiy VV, Balasubramanian G, Bondarenko VE, Morales MJ. Toxicon 45 431-442 (2005)
  9. Is lipid bilayer binding a common property of inhibitor cysteine knot ion-channel blockers? Posokhov YO, Gottlieb PA, Morales MJ, Sachs F, Ladokhin AS. Biophys J 93 L20-2 (2007)
  10. Structural interactions of a voltage sensor toxin with lipid membranes. Mihailescu M, Krepkiy D, Milescu M, Gawrisch K, Swartz KJ, White S. Proc Natl Acad Sci U S A 111 E5463-70 (2014)
  11. The structure of spider toxin huwentoxin-II with unique disulfide linkage: evidence for structural evolution. Shu Q, Lu SY, Gu XC, Liang SP. Protein Sci 11 245-252 (2002)
  12. Solution structure of APETx1 from the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin. Chagot B, Diochot S, Pimentel C, Lazdunski M, Darbon H. Proteins 59 380-386 (2005)
  13. Modulation of Kv4.2 channels by a peptide isolated from the venom of the giant bird-eating tarantula Theraphosa leblondi. Ebbinghaus J, Legros C, Nolting A, Guette C, Celerier ML, Pongs O, Bähring R. Toxicon 43 923-932 (2004)
  14. S3b amino acid substitutions and ancillary subunits alter the affinity of Heteropoda venatoria toxin 2 for Kv4.3. DeSimone CV, Lu Y, Bondarenko VE, Morales MJ. Mol Pharmacol 76 125-133 (2009)
  15. Transient-outward K+ channel inhibition facilitates L-type Ca2+ current in heart. Wang Y, Cheng J, Tandan S, Jiang M, McCloskey DT, Hill JA. J Cardiovasc Electrophysiol 17 298-304 (2006)
  16. Manipulating Kv4.2 identifies a specific component of hippocampal pyramidal neuron A-current that depends upon Kv4.2 expression. Lauver A, Yuan LL, Jeromin A, Nadin BM, Rodríguez JJ, Davies HA, Stewart MG, Wu GY, Pfaffinger PJ. J Neurochem 99 1207-1223 (2006)
  17. Solution structure of two insect-specific spider toxins and their pharmacological interaction with the insect voltage-gated Na+ channel. Ferrat G, Bosmans F, Bosmans F, Tytgat J, Pimentel C, Chagot B, Gilles N, Nakajima T, Darbon H, Corzo G. Proteins 59 368-379 (2005)
  18. Effect of gating modifier toxins on membrane thickness: implications for toxin effect on gramicidin and mechanosensitive channels. Chen R, Chung SH. Toxins (Basel) 5 456-471 (2013)
  19. Leftward shift in the voltage-dependence for Ca2+ currents activation induced by a new toxin from Phoneutria reidyi (Aranae, Ctenidae) venom. Vieira LB, Pimenta AM, Richardson M, Bemquerer MP, Reis HJ, Cruz JS, Gomez MV, Santoro MM, Ferreira-de-Oliveira R, Figueiredo SG, Snutch TP, Cordeiro MN. Cell Mol Neurobiol 27 129-146 (2007)
  20. Solution structure of ADO1, a toxin extracted from the saliva of the assassin bug, Agriosphodrus dohrni. Bernard C, Corzo G, Adachi-Akahane S, Foures G, Kanemaru K, Furukawa Y, Nakajima T, Darbon H. Proteins 54 195-205 (2004)
  21. Jingzhaotoxin-35, a novel gating-modifier toxin targeting both Nav1.5 and Kv2.1 channels. Wei P, Xu C, Wu Q, Huang L, Liang S, Yuan C. Toxicon 92 90-96 (2014)
  22. Jingzhaotoxin-X, a gating modifier of Kv4.2 and Kv4.3 potassium channels purified from the venom of the Chinese tarantula Chilobrachys jingzhao. Deng M, Jiang L, Luo X, Tao H, Liang S. J Venom Anim Toxins Incl Trop Dis 26 e20190043 (2020)
  23. Molecular Diversity of Peptide Toxins in the Venom of Spider Heteropoda pingtungensis as Revealed by cDNA Library and Transcriptome Sequencing Analysis. Liao Q, Kong X, Luo G, Wu X, Li Y, Liu Q, Tang C, Liu Z. Toxins (Basel) 14 140 (2022)


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