NMR structure of μ-conotoxin GIIIC : leucine 18 induces local repacking of the N-terminus resulting in reduced NaV channel potency
| Autor: | David J. Adams, Rocio K. Finol-Urdaneta, David J. Craik, Justine M. Hill, Jeffrey R. McArthur, Peta J. Harvey, Dorien Van Lysebetten, Thomas Durek, Thomas S. Dash, Nyoman D. Kurniawan |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine μ-conotoxins Magnetic Resonance Spectroscopy Protein Conformation Pharmaceutical Science Peptide Sodium Channels Analytical Chemistry SUBTYPES Protein structure Drug Discovery Side chain Disulfides chemistry.chemical_classification mu-conotoxins Chemistry ARRANGEMENT BLOCKER INHIBITOR SODIUM-CHANNELS MUSCLE 3. Good health voltage-gated sodium channel blocker BINDING-SITE Chemistry (miscellaneous) Molecular Medicine Leucine SENSITIVITY Two-dimensional nuclear magnetic resonance spectroscopy Sodium Channel Blockers Stereochemistry Article lcsh:QD241-441 Structure-Activity Relationship 03 medical and health sciences lcsh:Organic chemistry Protein Interaction Domains and Motifs Amino Acid Sequence Physical and Theoretical Chemistry Binding site protein structure Sodium channel Organic Chemistry Biology and Life Sciences NMR N-terminus 030104 developmental biology Conotoxins Peptides TETRODOTOXIN |
| Zdroj: | MOLECULES Molecules, Vol 23, Iss 10, p 2715 (2018) Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry Molecules Volume 23 Issue 10 |
| ISSN: | 1420-3049 |
| Popis: | &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 (NaV), albeit with ~2.5-fold lower potency than GIIIA. GIIIC exhibited a lower potency of inhibition of NaV1.4 channels, but the same NaV 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. |
| Databáze: | OpenAIRE |
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