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Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds

Krisztina Fehér UGent, István Timári, Kinga Rákosi, János Szolomájer, Tünde Z Illyés, Adam Bartok, Zoltan Varga, Gyorgy Panyi, Gábor K Tóth and Katalin E Kövéer (2016) CHEMICAL SCIENCE. 7(4). p.2666-2673
abstract
Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin containing four disulfide bridges, is a high affinity blocker of the voltage-gated potassium channel Kv1.3, but also blocks Kv1.2. To improve potential therapeutic use of the toxin, we have designed a double substituted analog, [N17A/F32T]-AnTx, which showed comparable Kv1.3 affinity to the wild-type peptide, but also a 2500-fold increase in the selectivity for Kv1.3 over Kv1.2. In the present study we have achieved the chemical synthesis of a Sec-analog in which all cysteine (Cys) residues have been replaced by selenocysteine (Sec) forming four diselenide bonds. To the best of our knowledge this is the first time to replace, by chemical synthesis, all disulfide bonds with isosteric diselenides in a peptide/protein. Gratifyingly, the key pharmacological properties of the Sec-[N17A/F32T]-AnTx are retained since the peptide is functionally active. We also propose here a combined experimental and theoretical approach including NOE- and Se-77-based NMR supplemented by MD simulations for conformational and dynamic characterization of the Sec-[N17A/F32T]-AnTx. Using this combined approach allowed us to attain unequivocal assignment of all four diselenide bonds and supplemental MD simulations allowed characterization of the conformational dynamics around each disulfide/diselenide bridge.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
HETERONUCLEAR COUPLING-CONSTANTS, EXCHANGE BROADENED SIGNALS, PARTICLE, MESH EWALD, MOLECULAR-DYNAMICS, K+ CHANNEL, AUTOIMMUNE-DISEASES, SCORPION TOXIN, T-LYMPHOCYTES, SIMULATIONS, KV1.3
journal title
CHEMICAL SCIENCE
Chem. Sci.
volume
7
issue
4
pages
2666 - 2673
Web of Science type
Article
Web of Science id
000372614800025
JCR category
CHEMISTRY, MULTIDISCIPLINARY
JCR impact factor
8.668 (2016)
JCR rank
17/166 (2016)
JCR quartile
1 (2016)
ISSN
2041-6520
2041-6539
DOI
10.1039/c5sc03995a
language
English
UGent publication?
yes
classification
A1
additional info
the first three authors contributed equally to this work
copyright statement
I have retained and own the full copyright for this publication
id
8522492
handle
http://hdl.handle.net/1854/LU-8522492
date created
2017-06-06 06:48:25
date last changed
2017-06-27 14:14:15
@article{8522492,
  abstract     = {Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin containing four disulfide bridges, is a high affinity blocker of the voltage-gated potassium channel Kv1.3, but also blocks Kv1.2. To improve potential therapeutic use of the toxin, we have designed a double substituted analog, [N17A/F32T]-AnTx, which showed comparable Kv1.3 affinity to the wild-type peptide, but also a 2500-fold increase in the selectivity for Kv1.3 over Kv1.2. In the present study we have achieved the chemical synthesis of a Sec-analog in which all cysteine (Cys) residues have been replaced by selenocysteine (Sec) forming four diselenide bonds. To the best of our knowledge this is the first time to replace, by chemical synthesis, all disulfide bonds with isosteric diselenides in a peptide/protein. Gratifyingly, the key pharmacological properties of the Sec-[N17A/F32T]-AnTx are retained since the peptide is functionally active. We also propose here a combined experimental and theoretical approach including NOE- and Se-77-based NMR supplemented by MD simulations for conformational and dynamic characterization of the Sec-[N17A/F32T]-AnTx. Using this combined approach allowed us to attain unequivocal assignment of all four diselenide bonds and supplemental MD simulations allowed characterization of the conformational dynamics around each disulfide/diselenide bridge.},
  author       = {Feh{\'e}r, Krisztina and Tim{\'a}ri, Istv{\'a}n and R{\'a}kosi, Kinga and Szolom{\'a}jer, J{\'a}nos and Illy{\'e}s, T{\"u}nde Z and Bartok, Adam and Varga, Zoltan and Panyi, Gyorgy and T{\'o}th, G{\'a}bor K and K{\"o}v{\'e}er, Katalin E},
  issn         = {2041-6520},
  journal      = {CHEMICAL SCIENCE},
  keyword      = {HETERONUCLEAR COUPLING-CONSTANTS,EXCHANGE BROADENED SIGNALS,PARTICLE,MESH EWALD,MOLECULAR-DYNAMICS,K+ CHANNEL,AUTOIMMUNE-DISEASES,SCORPION TOXIN,T-LYMPHOCYTES,SIMULATIONS,KV1.3},
  language     = {eng},
  number       = {4},
  pages        = {2666--2673},
  title        = {Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds},
  url          = {http://dx.doi.org/10.1039/c5sc03995a},
  volume       = {7},
  year         = {2016},
}

Chicago
Fehér, Krisztina, István Timári, Kinga Rákosi, János Szolomájer, Tünde Z Illyés, Adam Bartok, Zoltan Varga, Gyorgy Panyi, Gábor K Tóth, and Katalin E Kövéer. 2016. “Probing Pattern and Dynamics of Disulfide Bridges Using Synthesis and NMR of an Ion Channel Blocker Peptide Toxin with Multiple Diselenide Bonds.” Chemical Science 7 (4): 2666–2673.
APA
Fehér, K., Timári, I., Rákosi, K., Szolomájer, J., Illyés, T. Z., Bartok, A., Varga, Z., et al. (2016). Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds. CHEMICAL SCIENCE, 7(4), 2666–2673.
Vancouver
1.
Fehér K, Timári I, Rákosi K, Szolomájer J, Illyés TZ, Bartok A, et al. Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds. CHEMICAL SCIENCE. 2016;7(4):2666–73.
MLA
Fehér, Krisztina, István Timári, Kinga Rákosi, et al. “Probing Pattern and Dynamics of Disulfide Bridges Using Synthesis and NMR of an Ion Channel Blocker Peptide Toxin with Multiple Diselenide Bonds.” CHEMICAL SCIENCE 7.4 (2016): 2666–2673. Print.