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1yi5

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Crystal structure of the a-cobratoxin-AChBP complexCrystal structure of the a-cobratoxin-AChBP complex

Structural highlights

1yi5 is a 10 chain structure with sequence from Lymnaea stagnalis and Naja siamensis. The November 2005 RCSB PDB Molecule of the Month feature on Acetylcholine Receptor by David S. Goodsell is 10.2210/rcsb_pdb/mom_2005_11. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[ACHP_LYMST] Binds to acetylcholine. Modulates neuronal synaptic transmission. [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]

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 crystal structure of the snake long alpha-neurotoxin, alpha-cobratoxin, bound to the pentameric acetylcholine-binding protein (AChBP) from Lymnaea stagnalis, was solved from good quality density maps despite a 4.2 A overall resolution. The structure unambiguously reveals the positions and orientations of all five three-fingered toxin molecules inserted at the AChBP subunit interfaces and the conformational changes associated with toxin binding. AChBP loops C and F that border the ligand-binding pocket move markedly from their original positions to wrap around the tips of the toxin first and second fingers and part of its C-terminus, while rearrangements also occur in the toxin fingers. At the interface of the complex, major interactions involve aromatic and aliphatic side chains within the AChBP binding pocket and, at the buried tip of the toxin second finger, conserved Phe and Arg residues that partially mimic a bound agonist molecule. Hence this structure, in revealing a distinctive and unpredicted conformation of the toxin-bound AChBP molecule, provides a lead template resembling a resting state conformation of the nicotinic receptor and for understanding selectivity of curaremimetic alpha-neurotoxins for the various receptor species.

Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors.,Bourne Y, Talley TT, Hansen SB, Taylor P, Marchot P EMBO J. 2005 Apr 20;24(8):1512-22. Epub 2005 Mar 24. PMID:15791209[19]

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

See Also

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. ↑ Bourne Y, Talley TT, Hansen SB, Taylor P, Marchot P. Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J. 2005 Apr 20;24(8):1512-22. Epub 2005 Mar 24. PMID:15791209

1yi5, resolution 4.20Å

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