Structure-activity relationships of ω-Agatoxin IVA in lipid membranes.

To analyze structural features of ω-Aga IVA, a gating modifier toxin from spider venom, we here investigated the NMR solution structure of ω-Aga IVA within DPC micelles. Under those conditions, the Cys-rich central region of ω-Aga IVA still retains the inhibitor Cys knot motif with three short antiparallel β-strands seen in water. However, 15N HSQC spectra of ω-Aga IVA within micelles revealed that there are radical changes to the toxin's C-terminal tail and several loops upon binding to micelles. The C-terminal tail of ω-Aga IVA appears to assume a β-turn like conformation within micelles, though it is disordered in water. Whole-cell patch clamp studies with several ω-Aga IVA analogs indicate that both the hydrophobic C-terminal tail and an Arg patch in the core region of ω-Aga IVA are critical for Cav2.1 blockade. These results suggest that the membrane environment stabilizes the structure of the toxin, enabling it to act in a manner similar to other gating modifier toxins, though its mode of interaction with the membrane and the channel is unique. Copyright © 2016 Elsevier Inc. All rights reserved.

Citation

Jae Ha Ryu, Hoi Jong Jung, Shiro Konishi, Ha Hyung Kim, Zee-Yong Park, Jae Il Kim. Structure-activity relationships of ω-Agatoxin IVA in lipid membranes. Biochemical and biophysical research communications. 2017 Jan 01;482(1):170-175

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PMID: 27838299

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