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Title: Structure-activity relationships of ω-Agatoxin IVA in lipid membranes

Abstract

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, {sup 15}N 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. - Highlights: • The NMR structure of ω-Aga IVA in DPC micelles is determined. • ω-Aga IVA stabilized its C-terminal tail with a β-turn structure within micelles. •more » Both the C-terminal tail and Arg patch play a crucial role for blocking Cav2.1.« less

Authors:
;  [1];  [2];  [3];  [1];  [1]
  1. School of Life Sciences, Gwangju Institute of Science and Technology, 123, Cheomdangwagi-ro, Buk-gu, Gwangju (Korea, Republic of)
  2. Department of Neurophysiology, Kagawa School of Pharmaceutical Sciences and Institute of Neuroscience, Tokushima Bunri University, 1314–1 Shido, Sanuki-shi, Kagawa, 769–2193 (Japan)
  3. College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul (Korea, Republic of)
Publication Date:
OSTI Identifier:
22696745
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 482; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; MATHEMATICAL SOLUTIONS; MEMBRANES; NITROGEN 15; NUCLEAR MAGNETIC RESONANCE; STRUCTURE-ACTIVITY RELATIONSHIPS; TOXINS

Citation Formats

Ryu, Jae Ha, Jung, Hoi Jong, Konishi, Shiro, Kim, Ha Hyung, Park, Zee-Yong, and Kim, Jae Il, E-mail: jikim@gist.ac.kr. Structure-activity relationships of ω-Agatoxin IVA in lipid membranes. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2016.11.025.
Ryu, Jae Ha, Jung, Hoi Jong, Konishi, Shiro, Kim, Ha Hyung, Park, Zee-Yong, & Kim, Jae Il, E-mail: jikim@gist.ac.kr. Structure-activity relationships of ω-Agatoxin IVA in lipid membranes. United States. doi:10.1016/J.BBRC.2016.11.025.
Ryu, Jae Ha, Jung, Hoi Jong, Konishi, Shiro, Kim, Ha Hyung, Park, Zee-Yong, and Kim, Jae Il, E-mail: jikim@gist.ac.kr. Sun . "Structure-activity relationships of ω-Agatoxin IVA in lipid membranes". United States. doi:10.1016/J.BBRC.2016.11.025.
@article{osti_22696745,
title = {Structure-activity relationships of ω-Agatoxin IVA in lipid membranes},
author = {Ryu, Jae Ha and Jung, Hoi Jong and Konishi, Shiro and Kim, Ha Hyung and Park, Zee-Yong and Kim, Jae Il, E-mail: jikim@gist.ac.kr},
abstractNote = {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, {sup 15}N 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. - Highlights: • The NMR structure of ω-Aga IVA in DPC micelles is determined. • ω-Aga IVA stabilized its C-terminal tail with a β-turn structure within micelles. • Both the C-terminal tail and Arg patch play a crucial role for blocking Cav2.1.},
doi = {10.1016/J.BBRC.2016.11.025},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 482,
place = {United States},
year = {2017},
month = {1}
}