6OHX

Solution structure of scorpion Hottentotta jayakari venom toxin Hj1a

Summary for 6OHX

• Entry DOI: 10.2210/pdb6ohx/pdb
• NMR Information: BMRB: 30598
• Descriptor: Venom toxin Hj1a (1 entity in total)
• Functional Keywords: sodium-gated ion channel, toxin
• Biological source: Hottentotta jayakari
• Total number of polymer chains: 1
• Total formula weight: 7559.60

Authors

Chin, Y.K.-Y.,Chow, C.Y.,King, G.F. (deposition date: 2019-04-08, release date: 2020-02-12, Last modification date: 2024-10-23)

Primary citation

Chow, C.Y.,Chin, Y.K.,Walker, A.A.,Guo, S.,Blomster, L.V.,Ward, M.J.,Herzig, V.,Rokyta, D.R.,King, G.F.
Venom Peptides with Dual Modulatory Activity on the Voltage-Gated Sodium Channel NaV1.1 Provide Novel Leads for Development of Antiepileptic Drugs.
Acs Pharmacol Transl Sci, 3:119-134, 2020

PubMed Abstract: Voltage-gated sodium (Na) channels play a fundamental role in normal neurological function, especially via the initiation and propagation of action potentials. The Na1.1 subtype is found in inhibitory interneurons of the brain and it is essential for maintaining a balance between excitation and inhibition in neuronal networks. Heterozygous loss-of-function mutations of , the gene encoding Na1.1, underlie Dravet syndrome (DS), a severe pediatric epilepsy. We recently demonstrated that selective inhibition of Na1.1 inactivation prevents seizures and premature death in a mouse model of DS. Thus, selective modulators of Na1.1 might be useful therapeutics for treatment of DS as they target the underlying molecular deficit. Numerous scorpion-venom peptides have been shown to modulate the activity of Na channels, but little is known about their activity at Na1.1. Here we report the isolation, sequence, three-dimensional structure, recombinant production, and functional characterization of two peptidic modulators of Na1.1 from venom of the buthid scorpion . These peptides, Hj1a and Hj2a, are potent agonists of Na1.1 (EC of 17 and 32 nM, respectively), and they present dual α/β activity by modifying both the activation and inactivation properties of the channel. NMR studies of rHj1a indicate that it adopts a cystine-stabilized αβ fold similar to known scorpion toxins. Although Hj1a and Hj2a have only limited selectivity for Na1.1, their unusual dual mode of action provides an alternative approach to the development of selective Na1.1 modulators for the treatment of DS.

PubMed: 32259093
DOI: 10.1021/acsptsci.9b00079

Experimental method

SOLUTION NMR