1zyv

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Crystal Structure Of Mutant K8DP9SR58KV59G Of Scorpion alpha-Like Neurotoxin Bmk M1 From Buthus Martensii Karsch

Structural highlights

1zyv is a 1 chain structure with sequence from Mesobuthus martensii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.5Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SCM1_MESMA Alpha toxins bind voltage-independently at site-3 of sodium channels (Nav) and inhibit the inactivation of the activated channels thereby blocking neuronal transmission. This toxin is active against both mammals and insects, and is classified as an alpha-like toxin. It is active on Nav1.2/SCN2A (EC(50)=139-252 nM), Nav1.3/SCN3A (EC(50)=565 nM), Nav1.4/SCN4A and Nav1.5/SCN5A (EC(50)=195-500 nM), Nav1.6/SCN8A (EC(50)=214 nM), and drosophila DmNav1 (EC(50)=30 nM) (PubMed:11322948, PubMed:12705833, PubMed:15677695, PubMed:19162162, PubMed:20678086). In mNav1.6/SCN8A, the toxin induces a large increase in both transient and persistent currents, which correlates with a prominent reduction in the fast component of inactivating current (PubMed:20678086). In rNav1.2/SCN2A and rNav1.3/SCN3A, toxin-increased currents is much smaller (PubMed:19162162, PubMed:20678086). Moreover, the toxin only accelerates the slow inactivation development and delay recovery of mNav1.6/SCN8A through binding to the channel in the open state (PubMed:20678086). Is 6-fold more toxic than BmK-M2. In vivo, intrahippocampal injection into rat induces epileptiform responses (PubMed:16229835). In addition, intraplantar injection into rat induces spontaneous nociception and hyperalgesia (PubMed:14554105).[1] [2] [3] [4] [5] [6] [7]

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

Scorpion alpha-like toxins are proteins that act on mammalian and insect voltage-gated Na+ channels. Therefore, these toxins constitute an excellent target for examining the foundations that underlie their target specificity. With this motive we dissected the role of six critical amino acids located in the five-residue reverse turn (RT) and C-tail (CT) of the scorpion alpha-like toxin BmK M1. These residues were individually substituted resulting in 11 mutants and were subjected to a bioassay on mice, an electrophysiological characterization on three cloned voltage-gated Na+ channels (Nav1.2, Nav1.5 and para), a CD analysis and X-ray crystallography. The results reveal two molecular sites, a couplet of residues (8-9) in the RT and a hydrophobic surface consisting of residues 57 and 59-61 in the CT, where the substitution with specific residues can redirect the alpha-like characteristics of BmK M1 to either total insect or much higher mammal specificity. Crystal structures reveal that the pharmacological ramification of these mutants is accompanied by the reshaping of the 3D structure surrounding position 8. Furthermore, our results also reveal that residues 57 and 59-61, located at the CT, enclose the critical residue 58 in order to form a hydrophobic "gasket". Mutants of BmK M1 that interrupt this hydrophobic surface significantly gain insect selectivity.

Structural basis for the voltage-gated Na+ channel selectivity of the scorpion alpha-like toxin BmK M1.,Ye X, Bosmans F, Li C, Zhang Y, Wang DC, Tytgat J J Mol Biol. 2005 Nov 4;353(4):788-803. Epub 2005 Sep 22. PMID:16209876[8]

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

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References

  1. ↑ Goudet C, Huys I, Clynen E, Schoofs L, Wang DC, Waelkens E, Tytgat J. Electrophysiological characterization of BmK M1, an alpha-like toxin from Buthus martensi Karsch venom. FEBS Lett. 2001 Apr 20;495(1-2):61-5. PMID:11322948
  2. ↑ Wang CG, Gilles N, Hamon A, Le Gall F, Stankiewicz M, Pelhate M, Xiong YM, Wang DC, Chi CW. Exploration of the functional site of a scorpion alpha-like toxin by site-directed mutagenesis. Biochemistry. 2003 Apr 29;42(16):4699-708. PMID:12705833 doi:http://dx.doi.org/10.1021/bi0270438
  3. ↑ Bai ZT, Zhang XY, Ji YH. Fos expression in rat spinal cord induced by peripheral injection of BmK I, an alpha-like scorpion neurotoxin. Toxicol Appl Pharmacol. 2003 Oct 1;192(1):78-85. PMID:14554105 doi:10.1016/s0041-008x(03)00260-6
  4. ↑ Liu LH, Bosmans F, Maertens C, Zhu RH, Wang DC, Tytgat J. Molecular basis of the mammalian potency of the scorpion alpha-like toxin, BmK M1. FASEB J. 2005 Apr;19(6):594-6. PMID:15677695 doi:10.1096/fj.04-2485fje
  5. ↑ Bai ZT, Zhao R, Zhang XY, Chen J, Liu T, Ji YH. The epileptic seizures induced by BmK I, a modulator of sodium channels. Exp Neurol. 2006 Jan;197(1):167-76. PMID:16229835 doi:10.1016/j.expneurol.2005.09.006
  6. ↑ Zhu MM, Tan M, Cheng HW, Ji YH. The alpha-like scorpion toxin BmK I enhances membrane excitability via persistent sodium current by preventing slow inactivation and deactivation of rNav1.2a expressed in Xenopus Oocytes. Toxicol In Vitro. 2009 Jun;23(4):561-8. PMID:19162162 doi:10.1016/j.tiv.2008.12.022
  7. ↑ He H, Liu Z, Dong B, Zhou J, Zhu H, Ji Y. Molecular determination of selectivity of the site 3 modulator (BmK I) to sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-induced neuronal hyperexcitability. Biochem J. 2010 Oct 15;431(2):289-98. PMID:20678086 doi:10.1042/BJ20100517
  8. ↑ Ye X, Bosmans F, Li C, Zhang Y, Wang DC, Tytgat J. Structural basis for the voltage-gated Na+ channel selectivity of the scorpion alpha-like toxin BmK M1. J Mol Biol. 2005 Nov 4;353(4):788-803. Epub 2005 Sep 22. PMID:16209876 doi:10.1016/j.jmb.2005.08.068

Contents


PDB ID 1zyv

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