Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin

Xu, Hui; Li, Tianbo; Rohou, Alexis; Arthur, Christopher P.; Tzakoniati, Foteini; Wong, Evera; Estevez, Alberto; Kugel, Christine; Franke, Yvonne; Chen, Jun; Ciferri, Claudio; Hackos, David H.; Koth, Christopher M.; Payandeh, Jian

doi:10.1016/j.cell.2018.12.018

Cited by 162 publications

(325 citation statements)

References 68 publications

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“…Notably, the key Na V PaS contact residues are not conserved in human Na V channels, which explains why Dc1a is insect‐selective . CryoEM and X‐ray crystallography have also been used recently to solve the structure of the complex formed between protoxin‐II, a spider‐venom knottin, and a chimeric bacterial/human Na V channel . These Na V channel‐knottin structures not only provide detailed information about the molecular basis by which these spider toxins allosterically modulate Na V channel activity, but they provide an opportunity for structure‐based rational design of knottins that are not only insect‐selective, but which target pest insects without harming beneficial species.…”

Section: Spider Knottins Allosterically Modulate Ion Channel Functionmentioning

confidence: 99%

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

King

2019

Pest Management Science

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Spider venoms are complex chemical arsenals that contain a rich variety of insecticidal toxins. However, the major toxin class in many spider venoms is disulfide‐rich peptides known as knottins. The knotted three‐dimensional fold of these mini‐proteins provides them with exceptional chemical and thermal stability as well as resistance to proteases. In contrast with other bioinsecticides, which are often slow‐acting, spider knottins are fast‐acting neurotoxins. In addition to being potently insecticidal, some knottins have exceptional taxonomic selectivity, being lethal to key agricultural pests but innocuous to vertebrates and beneficial insects such as bees. The intrinsic oral activity of these peptides, combined with the ability of aerosolized knottins to penetrate insect spiracles, has enabled them to be developed commercially as eco‐friendly bioinsecticides. Moreover, it has been demonstrated that spider‐knottin transgenes can be used to engineer faster‐acting entomopathogens and insect‐resistant crops. © 2019 Society of Chemical Industry

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Section: Spider Knottins Allosterically Modulate Ion Channel Functionmentioning

confidence: 99%

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

King

2019

Pest Management Science

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“…For photocrosslinking experiments and to reduce the complexity of working with full-length Nav1.7, we employed a chimera strategy in which hNav1.7 VSD2 sequences were fused to a NavAb scaffold to permit high-level expression and production of stable, purified protein (Ahuja et al, 2015;Xu et al, 2019). This chimeric channel is referred to as VSD2-NavAb and it was used in structural studies of Protoxin-II inhibition (Xu et al, 2019). A similar chimeric channel based on VSD2 and NavAb has exhibited binding to HwTx-IV in surface plasmon resonance assays (Rajamani et al, 2017).…”

Section: Design and Purification Of A Chimeric Vsd2-navabmentioning

confidence: 99%

“…Residue 27 potentially interacts with S3. The VSD2-NavAb structure originates from the cryo-EM studies of VSD2-NavAb in complex with ICK peptide Protoxin-II (Xu et al, 2019). mutagenesis studies probing the HwTx-IV binding site on Nav1.7, which showed that E753 in the VSD2 S1-S2 loop and E811 in VSD2 S3 were determined to be important residues (Xiao et al, 2011).…”

Section: Design and Purification Of A Chimeric Vsd2-navabmentioning

confidence: 99%

“…For example, X-ray crystallographic studies have elucidated the binding interactions of aryl sulfonamide inhibitors on Nav1.7, using a chimeric strategy in which the VSD4 of Nav1.7 was fused to the pore of the bacterial Arcobacter butzleri Nav channel (NavAb). This strategy enabled high-level production of channel domains suitable for structural studies (Ahuja et al, 2015) and a similar strategy led to the elucidation of the mechanism of VSD2 modulation by inhibitory cystine knot (ICK) peptide Protoxin-II (Xu et al, 2019). High-resolution cryoelectron microscopy (cryo-EM) was employed to map the binding site of the desert bush spider toxin Dc1a onto VSD2 of the American cockroach Nav channel, NavPaS (Shen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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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“…All α subunits share high sequence conservation and nearly identical structure topology. Thus, the design of isoform-selective Nav modulators is challenging [65]. Two centipede peptides, µ-SLPTX 3 -Ssm2a and µ-SLPTX 3 -Ssm3a, were identified as specific Nav blockers [42,66].…”

Section: Voltage-gated Sodium Channel (Nav) Blockermentioning

confidence: 99%

Centipede Venom Peptides Acting on Ion Channels

Chu

Qiu

2020

Toxins

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Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of low-molecular-weight peptide toxins that have evolved to target voltage-gated ion channels to interfere with the central system of prey and produce pain or paralysis for efficient hunting. Peptide toxins usually contain several intramolecular disulfide bonds, which confer chemical, thermal and biological stability. In addition, centipede peptides generally have novel structures and high potency and specificity and therefore hold great promise both as diagnostic tools and in the treatment of human disease. Here, we review the centipede peptide toxins with reported effects on ion channels, including Nav, Kv, Cav and the nonselective cation channel polymodal transient receptor potential vanilloid 1 (TRPV1).

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Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin

Cited by 162 publications

References 68 publications

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

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

Centipede Venom Peptides Acting on Ion Channels

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