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  • SyncroPatch 384/768i

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2019 - Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7

icon sp96  SyncroPatch 768PE (a predecessor model of the SyncroPatch 384/768i) Publication in Cell Chemical Biology (2019)

Authors: 
Tzakoniati F., Xu H., Li T., Garcia N., Kugel C., Payandeh J., Koth C.M., Tate E.W.

Journal: 
Cell Chemical Biology (2019) In Press, corrected proof doi.org/10.1016/j.chembiol.2019.10.011


Highlights: 

  • Development of six potent diazirine-containing photoprobes based on Huwentoxin-IV

  • Photoprobes specifically photolabel purified bacterial-Nav1.7 VSD2 chimeric channels

  • Proteomic mass spectrometry identifies binding site on S1-S2 loop and S3 helix

  • Proposed model of HwTx-IV binding reveals importance of K27 and R29

 

Summary: 

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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