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Structure paper

TitleStructural basis for the modulation of voltage-gated sodium channels by animal toxins.
Journal, issue, pagesScience, Vol. 362, Issue 6412, Year 2018
Publish dateOct 19, 2018
AuthorsHuaizong Shen / Zhangqiang Li / Yan Jiang / Xiaojing Pan / Jianping Wu / Ben Cristofori-Armstrong / Jennifer J Smith / Yanni K Y Chin / Jianlin Lei / Qiang Zhou / Glenn F King / Nieng Yan /
PubMed AbstractAnimal toxins that modulate the activity of voltage-gated sodium (Na) channels are broadly divided into two categories-pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and ...Animal toxins that modulate the activity of voltage-gated sodium (Na) 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 Na channel NaPaS 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 VSD and the pore of NaPaS, 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 Na channel drugs.
External linksScience / PubMed:30049784
MethodsEM (single particle)
Resolution2.6 - 3.2 Å
Structure data

EMDB-6995, PDB-6a90:
Complex of voltage-gated sodium channel NavPaS from American cockroach Periplaneta americana and Dc1a
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-6996, PDB-6a91:
Complex of voltage-gated sodium channel NavPaS from American cockroach Periplaneta americana bound with saxitoxin and Dc1a
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-6997, PDB-6a95:
Complex of voltage-gated sodium channel NavPaS from American cockroach Periplaneta americana bound with tetrodotoxin and Dc1a
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

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

ChemComp-NA:
Unknown entry

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

ChemComp-9SL:
[(3aS,4R,10aS)-2,6-diamino-10,10-dihydroxy-3a,4,9,10-tetrahydro-3H,8H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate / neurotoxin*YM / Saxitoxin

ChemComp-HOH:
WATER / Water

ChemComp-9SR:
(1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name) / neurotoxin*YM / Tetrodotoxin

Source
  • periplaneta americana (American cockroach)
  • diguetia canities (spider)
KeywordsMEMBRANE PROTEIN/TOXIN / complex / sodium channel / toxin / MEMBRANE PROTEIN / MEMBRANE PROTEIN-TOXIN complex

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