Opening the Gates to Treatment
Targeting the voltage-gated ion channels may yield useful treatments in an array of disorders, such as pain, migraines, epilepsy, and cardiovascular and neurological disorders. Toxins that demonstrate Nav channel subtype selectivity have been suggested as potential early drug leads.1
The Protoxins, ProTx-I and ProTx-II, were first isolated and characterized from the venom of the tarantula, Thrixopelma pruriens. These peptide toxins belong to the inhibitory cystine knot (ICK) family, which is known to interact with voltage-gated ion channels. Typically, toxins are not very selective in their interactions, presently making the search for a suitable drug candidate challenging. However, Protoxin-II (ProTx2), a 30-residue disulfide-rich peptide has been found to possess unusually high affinity and selectivity toward the human Nav1.7 channel.2
In a new publication in Cell, researchers from Genentech report their findings from visualizing ProTx-II in complex with Nav1.7 using cryoelectron microscopy (Cryo-EM) and X-ray crystallography. Within a voltage-gated ion channel, there is a voltage-sensor domain (VSD). The VSD is responsible for sensing and responding to the change in membrane potential across the channel and contains four helical subunits (S1-4) within four homologous domains.2,4,5,6 The helical subunits S5-6 are a part of the ion-conducting pathway.6 Positively charged Arginine guanidino groups are able to maintain their protons even when located deep within a membrane.3 The visualizations showed that ProTx-II uses arginine and lysine to target glutamic acid and aspartic acids in VSD2 through electrostatic interaction. It is able to engage with both the inactivated and deactivated states of VSD2. Furthermore, they found that ProTx-II prevents S4 movement through electrostatic modulation and ultimately blocks the S6 activation gate.2
We invite you to take a look at their full article here.
- M. Flinspach et al. Sci. Rep. 7, 39662 (2017).
- H. Xu et al., Cell, 176, 1 (2019).
- M. Sasaki, Science, 312 (2006).
- C.T. Armstrong, Nature Scientific Reports, 6, 21759 (2016).
- J. Payandeh et al., Nature, 475(7356), 353 (2011).
- Y. Yang et al., J Biol Chem., 288(19),13741 (2013).