Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Poisons* ; Voltage-Gated Sodium Channels*/metabolism; Batrachotoxins/metabolism ; Binding Sites ; Molecular Conformation

The poison dart toxin batrachotoxin is exceptional for its high potency and toxicity, and for its multifaceted modification of the function of voltage-gated sodium channels. By using cryogenic electron microscopy, we identify two homologous, but nonidentical receptor sites that simultaneously bind two molecules of toxin, one at the interface between Domains I and IV, and the other at the interface between Domains III and IV of the cardiac sodium channel. Together, these two bound toxin molecules stabilize α/π helical conformation in the S6 segments that gate the pore, and one of the bound BTX-B molecules interacts with the crucial Lys1421 residue that is essential for sodium conductance and selectivity via an apparent water-bridged hydrogen bond. Overall, our structure provides insight into batrachotoxin's potency, efficacy, and multifaceted functional effects on voltage-gated sodium channels via a dual receptor site mechanism.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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K08 HL145630 United States HL NHLBI NIH HHS; R01 GM117263 United States GM NIGMS NIH HHS; R01 HL112808 United States HL NHLBI NIH HHS; R35 NS111573 United States NS NINDS NIH HHS

0 (Batrachotoxins)
0 (Poisons)
0 (Voltage-Gated Sodium Channels)

Date Created: 20240315 Date Completed: 20240318 Latest Revision: 20240402

20240402

PMC10940626

10.1038/s41467-024-45958-w

38485923