Centruroides sculpturatus Ewing variant 2 toxin (CsE-v2) is a neurotoxin isolated from the venom of a scorpion native to the Arizona desert. The structure of CsE-v2 was solved in two different crystal forms using a combination of molecular replacement and multiple isomorphous replacement techniques. Crystals of CsE-v2 display a temperature-dependent, reversible-phase transition near room temperature. At lower temperature the space group changes from P3221 to P3121 with an approximate doubling of the C-axis. The small-cell structure, which has one molecule per asymmetric unit, has an R factor of 0.229 at 2.8 Å resolution. The large-cell structure has two molecules per asymmetric unit and was refined at 2.2 Å resolution to an R factor of 0.255. CsE-v2 is a rigid, compact structure with four intrachain disulfide bonds. The structure is similar to other long-chain β neurotoxins, and the largest differences occur in the last six residues. The high-resolution structure of CsE-v2 corrects an error in the reported C-terminal sequence; the terminal tripeptide sequence is Ser 64-Cys 65-Ser 66 rather than Ser 64-Ser 65-Cys 66. Comparison of CsE-v2 with long-chain α toxins reveals four insertions and one deletion, as well as additional residues at the N and C termini. Structural alignment of α and β toxins suggests that the primary distinguishing feature between the two classes is the length of the loop between the second and third strands in a three-strand β sheet. The shorter loop in α toxins exposes a critical lysine side chain, whereas the longer loop in β toxins buries the corresponding basic residue (either arginine or lysine)
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