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TitleDual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 2306, Year 2024
Publish dateMar 14, 2024
AuthorsLige Tonggu / Goragot Wisedchaisri / Tamer M Gamal El-Din / Michael J Lenaeus / Matthew M Logan / Tatsuya Toma / Justin Du Bois / Ning Zheng / William A Catterall /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:38485923 / PubMed Central
MethodsEM (single particle)
Resolution3.3 Å
Structure data

41071

8t6l

EMDB-41071, PDB-8t6l:
Cryo-EM structure of rat cardiac sodium channel NaV1.5 with batrachotoxin analog BTX-B
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM / POPC

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM


ChemComp, No image

ChemComp-YIJ:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • rattus norvegicus (Norway rat)
  • aequorea victoria (jellyfish)
KeywordsMEMBRANE PROTEIN / Ion channel / Sodium channel / Voltage-gated channel / Sodium transport

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