2I61: Depressant Anti-insect Neurotoxin, Lqhit2 From Leiurus Quinquestriatus Hebraeus

Citation:
Abstract
Scorpion depressant beta-toxins show high preference for insect voltage-gated sodium channels (Na(v)s) and modulate their activation. Although their pharmacological and physiological effects were described, their three-dimensional structure and bioactive surface have never been determined. We utilized an efficient system for expression of the depressant toxin LqhIT2 (from Leiurus quinquestriatushebraeus), mutagenized its entire exterior, and determined its X-ray structure at 1.2 A resolution. The toxin molecule is composed of a conserved cysteine-stabilized alpha/beta-core (core-globule), and perpendicular to it an entity constituted from the N and C-terminal regions (NC-globule). The surface topology and overall hydrophobicity of the groove between the core and NC-globules (N-groove) is important for toxin activity and plays a role in selectivity to insect Na(v)s. The N-groove is flanked by Glu24 and Tyr28, which belong to the "pharmacophore" of scorpion beta-toxins, and by the side-chains of Trp53 and Asn58 that are important for receptor site recognition. Substitution of Ala13 by Trp in the N-groove uncoupled activity from binding, suggesting that this region of the molecule is also involved in "voltage-sensor trapping", the mode of action that typifies scorpion beta-toxins. The involvement of the N-groove in recognition of the receptor site, which seems to require a defined topology, as well as in sensor trapping, which involves interaction with a moving channel region, is puzzling. On the basis of the mutagenesis studies we hypothesize that following binding to the receptor site, the toxin undergoes a conformational change at the N-groove region that facilitates the trapping of the voltage-sensor in its activated position.
PDB ID: 2I61Download
MMDB ID: 43392
PDB Deposition Date: 2006/8/27
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 1.2  Å
Source Organism:
Similar Structures:
Biological Unit for 2I61: monomeric; determined by author
Molecular Components in 2I61
Label Count Molecule
Protein (1 molecule)
1
Insect Toxin 2
Molecule annotation
Chemicals (9 molecules)
1
3
2
1
3
3
4
1
5
1
* Click molecule labels to explore molecular sequence information.

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