2gx1
Solution structure and alanine scan of a spider toxin that affects the activation of mammalian sodium channels
Structural highlights
FunctionTXMG5_MACGS Insect and vertebrate active toxin. Binds to site 4 of mammalian voltage-gated sodium channels and shifts the activation voltage of the mammalian Nav1.2a/SCN2A channel to more hyperpolarized voltages, whereas the insect channel, DmNav1 (para), is not affected. Competes for binding at site 3 of the insect sodium channel. Causes temporary paralysis when injected into lepidopteran larvae at 8.6 nmol/g. A low intracranial injection dose into mice causes lacrimation, closure of the eyes and sweating. A high injection dose causes extensive lacrimation and death.[1] Publication Abstract from PubMedMagi 5, from the hexathelid spider Macrothele gigas, is a 29-residue polypeptide containing three disulfide bridges. It binds specifically to receptor site 4 on mammalian voltage-gated sodium channels and competes with scorpion beta-toxins, such as Css IV from Centruroides suffusus suffusus. As a consequence, Magi 5 shifts the activation voltage of the mammalian rNav1.2a channel to more hyperpolarized voltages, whereas the insect channel, DmNav1, is not affected. To gain insight into toxin-channel interactions, Magi 5 and 23 analogues were synthesized. The three-dimensional structure of Magi 5 in aqueous solution was determined, and its voltage-gated sodium channel-binding surfaces were mapped onto this structure using data from electrophysiological measurements on a series of Ala-substituted analogues. The structure clearly resembles the inhibitor cystine knot structural motif, although the triple-stranded beta-sheet typically found in that motif is partially distorted in Magi 5. The interactive surface of Magi 5 toward voltage-gated sodium channels resembles in some respects the Janus-faced atracotoxins, with functionally important charged residues on one face of the toxin and hydrophobic residues on the other. Magi 5 also resembles the scorpion beta-toxin Css IV, which has distinct nonpolar and charged surfaces that are critical for channel binding and has a key Glu involved in voltage sensor trapping. These two distinct classes of toxin, with different amino acid sequences and different structures, may utilize similar groups of residues on their surface to achieve the common end of modifying voltage-gated sodium channel function. Solution structure and alanine scan of a spider toxin that affects the activation of mammalian voltage-gated sodium channels.,Corzo G, Sabo JK, Bosmans F, Billen B, Villegas E, Tytgat J, Norton RS J Biol Chem. 2007 Feb 16;282(7):4643-52. Epub 2006 Dec 5. PMID:17148449[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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