1lxg

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Solution structure of alpha-cobratoxin complexed with a cognate peptide (structure ensemble)Solution structure of alpha-cobratoxin complexed with a cognate peptide (structure ensemble)

Structural highlights

1lxg is a 2 chain structure with sequence from Naja kaouthia and Pacific electric ray. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[NXL1_NAJKA] The monomeric form binds with high affinity to muscular, Torpedo (muscle-type), and neuronal alpha-7 nicotinic acetylcholine receptors (nAChR). Has no effect on alpha-3/beta-2 nAChR. Causes paralysis by preventing acetylcholine binding to the nAChR. Does not show any blockade of the nicotine-evoked release of dopamine and does not affect ACh release. In mice lung cancer, causes reduction of tumor growth.[1] [2] [3] [4] [5] [6] [7] [8] [9] The homodimeric form binds with low affinity to Torpedo (muscle-type) and alpha-7 nAChRs, whereas it acquires the capacity to block alpha-3/beta-2 nAChRs.[10] [11] [12] [13] [14] [15] [16] [17] [18] [ACHA_TORCA] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The alpha18-mer peptide, spanning residues 181-198 of the Torpedo nicotinic acetylcholine receptor alpha1 subunit, contains key binding determinants for agonists and competitive antagonists. To investigate whether the alpha18-mer can bind other alpha-neurotoxins besides alpha-bungarotoxin, we designed a two-dimensional (1)H-(15)N heteronuclear single quantum correlation experiment to screen four related neurotoxins for their binding ability to the peptide. Of the four toxins tested (erabutoxin a, erabutoxin b, LSIII, and alpha-cobratoxin), only alpha-cobratoxin binds the alpha18-mer to form a 1:1 complex. The NMR solution structure of the alpha-cobratoxin.alpha18-mer complex was determined with a backbone root mean square deviation of 1.46 A. In the structure, alpha-cobratoxin contacts the alpha18-mer at the tips of loop I and II and through C-terminal cationic residues. The contact zone derived from the intermolecular nuclear Overhauser effects is in agreement with recent biochemical data. Furthermore, the structural models support the involvement of cation-pi interactions in stabilizing the complex. In addition, the binding screen results suggest that C-terminal cationic residues of alpha-bungarotoxin and alpha-cobratoxin contribute significantly to binding of the alpha18-mer. Finally, we present a structural model for nicotinic acetylcholine receptor-alpha-cobratoxin interaction by superimposing the alpha-cobratoxin.alpha18-mer complex onto the crystal structure of the acetylcholine-binding protein (Protein Data Bank code ).

NMR-based binding screen and structural analysis of the complex formed between alpha-cobratoxin and an 18-mer cognate peptide derived from the alpha 1 subunit of the nicotinic acetylcholine receptor from Torpedo californica.,Zeng H, Hawrot E J Biol Chem. 2002 Oct 4;277(40):37439-45. Epub 2002 Jul 19. PMID:12133834[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Osipov AV, Kasheverov IE, Makarova YV, Starkov VG, Vorontsova OV, Ziganshin RKh, Andreeva TV, Serebryakova MV, Benoit A, Hogg RC, Bertrand D, Tsetlin VI, Utkin YN. Naturally occurring disulfide-bound dimers of three-fingered toxins: a paradigm for biological activity diversification. J Biol Chem. 2008 May 23;283(21):14571-80. Epub 2008 Apr 1. PMID:18381281 doi:http://dx.doi.org/M802085200
  2. ↑ Kang S, Maelicke A. Fluorescein isothiocyanate-labeled alpha-cobratoxin. Biochemical characterization and interaction with acetylcholine receptor from Electrophorus electricus. J Biol Chem. 1980 Aug 10;255(15):7326-32. PMID:6771288
  3. ↑ Martin BM, Chibber BA, Maelicke A. The sites of neurotoxicity in alpha-cobratoxin. J Biol Chem. 1983 Jul 25;258(14):8714-22. PMID:6553056
  4. ↑ Alkondon M, Albuquerque EX. alpha-Cobratoxin blocks the nicotinic acetylcholine receptor in rat hippocampal neurons. Eur J Pharmacol. 1990 Dec 4;191(3):505-6. PMID:2086254
  5. ↑ Apel C, Ricny J, Wagner G, Wessler I. alpha-Bungarotoxin, kappa-bungarotoxin, alpha-cobratoxin and erabutoxin-b do not affect [3H]acetylcholine release from the rat isolated left hemidiaphragm. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;352(6):646-52. PMID:9053737
  6. ↑ Servent D, Winckler-Dietrich V, Hu HY, Kessler P, Drevet P, Bertrand D, Menez A. Only snake curaremimetic toxins with a fifth disulfide bond have high affinity for the neuronal alpha7 nicotinic receptor. J Biol Chem. 1997 Sep 26;272(39):24279-86. PMID:9305882
  7. ↑ Dajas-Bailador F, Costa G, Dajas F, Emmett S. Effects of alpha-erabutoxin, alpha-bungarotoxin, alpha-cobratoxin and fasciculin on the nicotine-evoked release of dopamine in the rat striatum in vivo. Neurochem Int. 1998 Oct;33(4):307-12. PMID:9840221
  8. ↑ Antil S, Servent D, Menez A. Variability among the sites by which curaremimetic toxins bind to torpedo acetylcholine receptor, as revealed by identification of the functional residues of alpha-cobratoxin. J Biol Chem. 1999 Dec 3;274(49):34851-8. PMID:10574958
  9. ↑ Grozio A, Paleari L, Catassi A, Servent D, Cilli M, Piccardi F, Paganuzzi M, Cesario A, Granone P, Mourier G, Russo P. Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development. Int J Cancer. 2008 Apr 15;122(8):1911-5. PMID:18067132 doi:http://dx.doi.org/10.1002/ijc.23298
  10. ↑ Osipov AV, Kasheverov IE, Makarova YV, Starkov VG, Vorontsova OV, Ziganshin RKh, Andreeva TV, Serebryakova MV, Benoit A, Hogg RC, Bertrand D, Tsetlin VI, Utkin YN. Naturally occurring disulfide-bound dimers of three-fingered toxins: a paradigm for biological activity diversification. J Biol Chem. 2008 May 23;283(21):14571-80. Epub 2008 Apr 1. PMID:18381281 doi:http://dx.doi.org/M802085200
  11. ↑ Kang S, Maelicke A. Fluorescein isothiocyanate-labeled alpha-cobratoxin. Biochemical characterization and interaction with acetylcholine receptor from Electrophorus electricus. J Biol Chem. 1980 Aug 10;255(15):7326-32. PMID:6771288
  12. ↑ Martin BM, Chibber BA, Maelicke A. The sites of neurotoxicity in alpha-cobratoxin. J Biol Chem. 1983 Jul 25;258(14):8714-22. PMID:6553056
  13. ↑ Alkondon M, Albuquerque EX. alpha-Cobratoxin blocks the nicotinic acetylcholine receptor in rat hippocampal neurons. Eur J Pharmacol. 1990 Dec 4;191(3):505-6. PMID:2086254
  14. ↑ Apel C, Ricny J, Wagner G, Wessler I. alpha-Bungarotoxin, kappa-bungarotoxin, alpha-cobratoxin and erabutoxin-b do not affect [3H]acetylcholine release from the rat isolated left hemidiaphragm. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;352(6):646-52. PMID:9053737
  15. ↑ Servent D, Winckler-Dietrich V, Hu HY, Kessler P, Drevet P, Bertrand D, Menez A. Only snake curaremimetic toxins with a fifth disulfide bond have high affinity for the neuronal alpha7 nicotinic receptor. J Biol Chem. 1997 Sep 26;272(39):24279-86. PMID:9305882
  16. ↑ Dajas-Bailador F, Costa G, Dajas F, Emmett S. Effects of alpha-erabutoxin, alpha-bungarotoxin, alpha-cobratoxin and fasciculin on the nicotine-evoked release of dopamine in the rat striatum in vivo. Neurochem Int. 1998 Oct;33(4):307-12. PMID:9840221
  17. ↑ Antil S, Servent D, Menez A. Variability among the sites by which curaremimetic toxins bind to torpedo acetylcholine receptor, as revealed by identification of the functional residues of alpha-cobratoxin. J Biol Chem. 1999 Dec 3;274(49):34851-8. PMID:10574958
  18. ↑ Grozio A, Paleari L, Catassi A, Servent D, Cilli M, Piccardi F, Paganuzzi M, Cesario A, Granone P, Mourier G, Russo P. Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development. Int J Cancer. 2008 Apr 15;122(8):1911-5. PMID:18067132 doi:http://dx.doi.org/10.1002/ijc.23298
  19. ↑ Zeng H, Hawrot E. NMR-based binding screen and structural analysis of the complex formed between alpha-cobratoxin and an 18-mer cognate peptide derived from the alpha 1 subunit of the nicotinic acetylcholine receptor from Torpedo californica. J Biol Chem. 2002 Oct 4;277(40):37439-45. Epub 2002 Jul 19. PMID:12133834 doi:10.1074/jbc.M205483200
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