scholarly journals Purification and Characterization of JZTx-14, a Potent Antagonist of Mammalian and Prokaryotic Voltage-Gated Sodium Channels

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 408 ◽  
Author(s):  
Jie Zhang ◽  
Dongfang Tang ◽  
Shuangyu Liu ◽  
Haoliang Hu ◽  
Songping Liang ◽  
...  

Exploring the interaction of ligands with voltage-gated sodium channels (NaVs) has advanced our understanding of their pharmacology. Herein, we report the purification and characterization of a novel non-selective mammalian and bacterial NaVs toxin, JZTx-14, from the venom of the spider Chilobrachys jingzhao. This toxin potently inhibited the peak currents of mammalian NaV1.2–1.8 channels and the bacterial NaChBac channel with low IC50 values (<1 µM), and it mainly inhibited the fast inactivation of the NaV1.9 channel. Analysis of NaV1.5/NaV1.9 chimeric channel showed that the NaV1.5 domain II S3–4 loop is involved in toxin association. Kinetics data obtained from studying toxin–NaV1.2 channel interaction showed that JZTx-14 was a gating modifier that possibly trapped the channel in resting state; however, it differed from site 4 toxin HNTx-III by irreversibly blocking NaV currents and showing state-independent binding with the channel. JZTx-14 might stably bind to a conserved toxin pocket deep within the NaV1.2–1.8 domain II voltage sensor regardless of channel conformation change, and its effect on NaVs requires the toxin to trap the S3–4 loop in its resting state. For the NaChBac channel, JZTx-14 positively shifted its conductance-voltage (G–V) and steady-state inactivation relationships. An alanine scan analysis of the NaChBac S3–4 loop revealed that the 108th phenylalanine (F108) was the key residue determining the JZTx-14–NaChBac interaction. In summary, this study provided JZTx-14 with potent but promiscuous inhibitory activity on both the ancestor bacterial NaVs and the highly evolved descendant mammalian NaVs, and it is a useful probe to understand the pharmacology of NaVs.

Neuroreport ◽  
2002 ◽  
Vol 13 (18) ◽  
pp. 2493-2498 ◽  
Author(s):  
Michael Schrey ◽  
Carolina Codina ◽  
Robert Kraft ◽  
Christian Beetz ◽  
Rolf Kalff ◽  
...  

2007 ◽  
Vol 77 (5) ◽  
pp. 855-863 ◽  
Author(s):  
Marian Seda ◽  
Francisco M. Pinto ◽  
Susan Wray ◽  
Cristina G. Cintado ◽  
Pedro Noheda ◽  
...  

2018 ◽  
Vol 293 (23) ◽  
pp. 9041-9052 ◽  
Author(s):  
Akello J. Agwa ◽  
Steve Peigneur ◽  
Chun Yuen Chow ◽  
Nicole Lawrence ◽  
David J. Craik ◽  
...  

Science ◽  
2018 ◽  
Vol 362 (6412) ◽  
pp. eaau2596 ◽  
Author(s):  
Huaizong Shen ◽  
Zhangqiang Li ◽  
Yan Jiang ◽  
Xiaojing Pan ◽  
Jianping Wu ◽  
...  

Animal toxins that modulate the activity of voltage-gated sodium (Nav) channels are broadly divided into two categories—pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Navchannel NavPaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSDIIand the pore of NavPaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na+access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Navchannel drugs.


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