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NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency

(2018) MOLECULES. 23(10).
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Abstract
mu-Conotoxins are potent and highly specific peptide blockers of voltage-gated sodium channels. In this study, the solution structure of mu-conotoxin GIIIC was determined using 2D NMR spectroscopy and simulated annealing calculations. Despite high sequence similarity, GIIIC adopts a three-dimensional structure that differs from the previously observed conformation of mu-conotoxins GIIIA and GIIIB due to the presence of a bulky, non-polar leucine residue at position 18. The side chain of L18 is oriented towards the core of the molecule and consequently the N-terminus is re-modeled and located closer to L18. The functional characterization of GIIIC defines it as a canonical mu-conotoxin that displays substantial selectivity towards skeletal muscle sodium channels (Na-V), albeit with similar to 2.5-fold lower potency than GIIIA. GIIIC exhibited a lower potency of inhibition of Na(V)1.4 channels, but the same Na-V selectivity profile when compared to GIIIA. These observations suggest that single amino acid differences that significantly affect the structure of the peptide do in fact alter its functional properties. Our work highlights the importance of structural factors, beyond the disulfide pattern and electrostatic interactions, in the understanding of the functional properties of bioactive peptides. The latter thus needs to be considered when designing analogues for further applications.
Keywords
mu-conotoxins, voltage-gated sodium channel blocker, NMR, protein structure, SODIUM-CHANNELS, BINDING-SITE, MUSCLE, TETRODOTOXIN, BLOCKER, ARRANGEMENT, SENSITIVITY, INHIBITOR, SUBTYPES

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MLA
Harvey, Peta J., et al. “NMR Structure of μ-Conotoxin GIIIC : Leucine 18 Induces Local Repacking of the N-Terminus Resulting in Reduced NaV Channel Potency.” MOLECULES, vol. 23, no. 10, 2018, doi:10.3390/molecules23102715.
APA
Harvey, P. J., Kurniawan, N. D., Finol-Urdaneta, R. K., McArthur, J. R., Van Lysebetten, D., Dash, T. S., … Craik, D. J. (2018). NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency. MOLECULES, 23(10). https://doi.org/10.3390/molecules23102715
Chicago author-date
Harvey, Peta J, Nyoman D Kurniawan, Rocio K Finol-Urdaneta, Jeffrey R McArthur, Dorien Van Lysebetten, Thomas S Dash, Justine M Hill, David J Adams, Thomas Durek, and David J Craik. 2018. “NMR Structure of μ-Conotoxin GIIIC : Leucine 18 Induces Local Repacking of the N-Terminus Resulting in Reduced NaV Channel Potency.” MOLECULES 23 (10). https://doi.org/10.3390/molecules23102715.
Chicago author-date (all authors)
Harvey, Peta J, Nyoman D Kurniawan, Rocio K Finol-Urdaneta, Jeffrey R McArthur, Dorien Van Lysebetten, Thomas S Dash, Justine M Hill, David J Adams, Thomas Durek, and David J Craik. 2018. “NMR Structure of μ-Conotoxin GIIIC : Leucine 18 Induces Local Repacking of the N-Terminus Resulting in Reduced NaV Channel Potency.” MOLECULES 23 (10). doi:10.3390/molecules23102715.
Vancouver
1.
Harvey PJ, Kurniawan ND, Finol-Urdaneta RK, McArthur JR, Van Lysebetten D, Dash TS, et al. NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency. MOLECULES. 2018;23(10).
IEEE
[1]
P. J. Harvey et al., “NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency,” MOLECULES, vol. 23, no. 10, 2018.
@article{8601313,
  abstract     = {{mu-Conotoxins are potent and highly specific peptide blockers of voltage-gated sodium channels. In this study, the solution structure of mu-conotoxin GIIIC was determined using 2D NMR spectroscopy and simulated annealing calculations. Despite high sequence similarity, GIIIC adopts a three-dimensional structure that differs from the previously observed conformation of mu-conotoxins GIIIA and GIIIB due to the presence of a bulky, non-polar leucine residue at position 18. The side chain of L18 is oriented towards the core of the molecule and consequently the N-terminus is re-modeled and located closer to L18. The functional characterization of GIIIC defines it as a canonical mu-conotoxin that displays substantial selectivity towards skeletal muscle sodium channels (Na-V), albeit with similar to 2.5-fold lower potency than GIIIA. GIIIC exhibited a lower potency of inhibition of Na(V)1.4 channels, but the same Na-V selectivity profile when compared to GIIIA. These observations suggest that single amino acid differences that significantly affect the structure of the peptide do in fact alter its functional properties. Our work highlights the importance of structural factors, beyond the disulfide pattern and electrostatic interactions, in the understanding of the functional properties of bioactive peptides. The latter thus needs to be considered when designing analogues for further applications.}},
  articleno    = {{2715}},
  author       = {{Harvey, Peta J and Kurniawan, Nyoman D and Finol-Urdaneta, Rocio K and McArthur, Jeffrey R and Van Lysebetten, Dorien and Dash, Thomas S and Hill, Justine M and Adams, David J and Durek, Thomas and Craik, David J}},
  issn         = {{1420-3049}},
  journal      = {{MOLECULES}},
  keywords     = {{mu-conotoxins,voltage-gated sodium channel blocker,NMR,protein structure,SODIUM-CHANNELS,BINDING-SITE,MUSCLE,TETRODOTOXIN,BLOCKER,ARRANGEMENT,SENSITIVITY,INHIBITOR,SUBTYPES}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{12}},
  title        = {{NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency}},
  url          = {{http://doi.org/10.3390/molecules23102715}},
  volume       = {{23}},
  year         = {{2018}},
}

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