Rational engineering defines a molecular switch that is essential for activity of spider-venom peptides against the analgesics target na(v)1.7

Klint, Julie K., Chin, Yanni K. -Y. and Mobli, Mehdi (2015) Rational engineering defines a molecular switch that is essential for activity of spider-venom peptides against the analgesics target na(v)1.7. Molecular Pharmacology, 88 6: 1002-1010. doi:10.1124/mol.115.100784


Author Klint, Julie K.
Chin, Yanni K. -Y.
Mobli, Mehdi
Title Rational engineering defines a molecular switch that is essential for activity of spider-venom peptides against the analgesics target na(v)1.7
Formatted title
Rational engineering defines a molecular switch that is essential for activity of spider-venom peptides against the analgesics target nav1.7
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
1521-0111
Publication date 2015-12
Sub-type Article (original research)
DOI 10.1124/mol.115.100784
Open Access Status Not Open Access
Volume 88
Issue 6
Start page 1002
End page 1010
Total pages 9
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2016
Language eng
Formatted abstract
Many spider-venom peptides are known to modulate the activity of the voltage-gated sodium (NaV) subtype 1.7 (NaV1.7) channel, which has emerged as a promising analgesic target. In particular, a class of spider-venom peptides (NaSpTx1) has been found to potently inhibit NaV1.7 (nanomolar IC50), and has been shown to produce analgesic effects in animals. However, one member of this family [µ-TRTX-Hhn2b (Hhn2b)] does not inhibit mammalian NaV channels expressed in dorsal root ganglia at concentrations up to 100 µM. This peptide is classified as a NaSpTx1 member by virtue of its cysteine spacing and sequence conservation over functionally important residues. Here, we have performed detailed structural and functional analyses of Hhn2b, leading us to identify two nonpharmacophore residues that contribute to human NaV1.7 (hNaV1.7) inhibition by nonoverlapping mechanisms. These findings allowed us to produce a double mutant of Hhn2b that shows nanomolar inhibition of hNaV1.7. Traditional structure/function analysis did not provide sufficient resolution to identify the mechanism underlying the observed gain of function. However, by solving the high-resolution structure of both the wild-type and mutant peptides using advanced multidimensional NMR experiments, we were able to uncover a previously unknown network of interactions that stabilize the pharmacophore region of this class of venom peptides. We further monitored the lipid binding properties of the peptides and identified that one of the key amino acid substitutions also selectively modulates the binding of the peptide to anionic lipids. These results will further aid the development of peptide-based analgesics for the treatment of chronic pain.
Keyword Sodium-channel antagonist
Extreme pain disorder
Voltage-sensor
Huwentoxin-IV
Tarantula toxins
Selenocosmia-huwena
Lipid-membranes
Erythromelalgia
Modulators
Mutations
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
 
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