Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNa V 1.7

Agwa, Akello J.; Lawrence, Nicole; Deplazes, Evelyne; Cheneval, Olivier; Chen, Rachel M.; Craik, David J.; Schroeder, Christina I.; Henriques, Sónia Troeira

doi:10.1016/j.bbamem.2017.01.020

Cited by 44 publications

(92 citation statements)

References 60 publications

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“…In addition, it suggests R29 as the residue that is close to N774 (N763 in this manuscript) in the cryo-EM structure (Shen et al, 2019). The proposed model illustrates the involvement of the membrane in the HwTx-IV-Nav1.7 complex even though the binding affinity of HwTx-IV to liposomes is weak compared with ProTx-II (Agwa et al, 2017). It further highlights that K27, a residue that is not the most prominent contributor to HwTx-IV inhibitory activity as concluded by alanine scanning mutagenesis studies (Revell et al, 2013), can interact with an acidic residue E811 on S3 helix, while allowing the crucial interaction of K32 with the same residue, and the hydrophobic surface (F6, W30, and Y33) to interact with the lipid bilayer.…”

Section: Design and Purification Of A Chimeric Vsd2-navabmentioning

confidence: 59%

Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7

Tzakoniati

Xu²,

Li³

et al. 2020

Cell Chemical Biology

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Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7; however, the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-S2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.

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Section: Design and Purification Of A Chimeric Vsd2-navabmentioning

confidence: 59%

Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7

Tzakoniati

Xu²,

Li³

et al. 2020

Cell Chemical Biology

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“…We also examined GMT affinity for POPC/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) (4:1) model membranes because phosphatidylserine phospholipids have frequently been used to mimic the influence of anionic moieties found on the outer leaflet of cell membranes (11,24,38,39). CcoTx-II, HnTx-IV, ProTx-I, and HwTx-IV showed preferential binding to POPC/POPS (4:1) over POPC lipid bilayers (0.045, 0.023, 0.049, and 0.013 P/L (mol/mol), respectively, for POPC/POPS compared with 0.023, 0.002, 0.029, and 0.004 P/L (mol/mol), respectively, for POPC).…”

Section: Gmt Amphipathicity and Na V Inhibitionmentioning

confidence: 99%

Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes

Agwa

Peigneur

Chow

et al. 2018

Journal of Biological Chemistry

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Gating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures and modulate activity of disease-relevant voltage-gated ion channels and are therefore being pursued as therapeutic leads. The amphipathic surface profile of GMTs has prompted the proposal that some GMTs simultaneously bind to the cell membrane and voltage-gated ion channels in a trimolecular complex. Here, we examined whether there is a relationship among spider GMT amphipathicity, membrane binding, and potency or selectivity for voltage-gated sodium (Na) channels. We used NMR spectroscopy and calculations to examine the structures and physicochemical properties of a panel of nine GMTs and deployed surface plasmon resonance to measure GMT affinity for lipids putatively found in proximity to Na channels. Electrophysiology was used to quantify GMT activity on Na1.7, an ion channel linked to chronic pain. Selectivity of the peptides was further examined against a panel of Na channel subtypes. We show that GMTs adsorb to the outer leaflet of anionic lipid bilayers through electrostatic interactions. We did not observe a direct correlation between GMT amphipathicity and affinity for lipid bilayers. Furthermore, GMT-lipid bilayer interactions did not correlate with potency or selectivity for Nas. We therefore propose that increased membrane binding is unlikely to improve subtype selectivity and that the conserved amphipathic GMT surface profile is an adaptation that facilitates simultaneous modulation of multiple Nas.

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“…Mutants of HwTx‐IV were developed to enhance its inhibitory activity over Na V 1.7, with (E1G,E4G,Y33W)HwTx‐IV showing a remarkable improvement in IC 50 from 27 to 0.4 nM in electrophysiology assays (Revell et al ., ). More recently, (E1G,E4G,F6W,Y33W)HwTx‐IV, a derivative of (E1G,E4G,Y33W)HwTx‐IV, was developed to enhance its binding to the lipidic membrane and this increased its potency at Na V 1.7 compared with native HwTx‐IV from IC 50 values of 32 to 7.5 nM in fluorescence imaging assays (Agwa et al ., ).…”

Section: Natural Toxins Targeting Nav Channels and Applications In Pamentioning

confidence: 97%

Sodium channels and pain: from toxins to therapies

Cardoso

Lewis

2017

British J Pharmacology

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Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNa V 1.7

Cited by 44 publications

References 60 publications

Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7

Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7

Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes

Sodium channels and pain: from toxins to therapies

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