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Papers of the Week


Papers: 16 Nov 2019 - 22 Nov 2019


Animal Studies, Pharmacology/Drug Development


2020 Mar 19


Cell Chem Biol


27


3

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

Authors

Tzakoniati F, Xu H, Li T, Garcia N, Kugel C, Payandeh J, Koth CM, Tate EW
Cell Chem Biol. 2020 Mar 19; 27(3):306-313.e4.
PMID: 31732432.

Abstract

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.