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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

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-dimensiona... Full description

Journal Title: MOLECULES 2018
Main Author: Harvey, Peta J
Other Authors: Kurniawan, Nyoman D , Finol - Urdaneta, Rocio K , Mcarthur, Jeffrey R , Van Lysebetten, Dorien , Dash, Thomas S , Hill, Justine M , Adams, David J , Durek, Thomas , Craik, David J
Format: Electronic Article Electronic Article
Language: English
Subjects:
Nmr
Created: 2018
ID: ISSN: 1420-3049 ; DOI: 10.3390/molecules2310.715
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title: NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency
format: Article
creator:
  • Harvey, Peta J
  • Kurniawan, Nyoman D
  • Finol - Urdaneta, Rocio K
  • Mcarthur, Jeffrey R
  • Van Lysebetten, Dorien
  • Dash, Thomas S
  • Hill, Justine M
  • Adams, David J
  • Durek, Thomas
  • Craik, David J
subjects:
  • Biology And Life Sciences
  • Chemistry
  • Mu-Conotoxins
  • Voltage-Gated Sodium Channel Blocker
  • Nmr
  • Protein Structure
  • Sodium-Channels
  • Binding-Site
  • Muscle
  • Tetrodotoxin
  • Blocker
  • Arrangement
  • Sensitivity
  • Inhibitor
  • Subtypes
ispartof: MOLECULES, 2018
description: 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.
language: eng
source:
identifier: ISSN: 1420-3049 ; DOI: 10.3390/molecules2310.715
fulltext: fulltext_linktorsrc
issn:
  • 1420 3049
  • 1420-3049
url: Link


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titleNMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency
creatorHarvey, Peta J ; Kurniawan, Nyoman D ; Finol - Urdaneta, Rocio K ; Mcarthur, Jeffrey R ; Van Lysebetten, Dorien ; Dash, Thomas S ; Hill, Justine M ; Adams, David J ; Durek, Thomas ; Craik, David J
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identifier ISSN: 1420-3049 ; DOI: 10.3390/molecules2310.715
subjectBiology And Life Sciences ; Chemistry ; Mu-Conotoxins ; Voltage-Gated Sodium Channel Blocker ; Nmr ; Protein Structure ; Sodium-Channels ; Binding-Site ; Muscle ; Tetrodotoxin ; Blocker ; Arrangement ; Sensitivity ; Inhibitor ; Subtypes
descriptionmu-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.
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titleNMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency
descriptionmu-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.
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abstractmu-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.
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