6nt4 | pdb_00006nt4

Cryo-EM structure of a human-cockroach hybrid Nav channel bound to alpha-scorpion toxin AaH2.

spinqualitylabelsall models 6nt4, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6nt4 is a 3 chain structure with sequence from American cockroach and Androctonus australis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, L0A, LHG, NAG, PEE, Y01 NonStd Res: NH2 Related: 6nt3 Gene: SCN9A, NENA (American cockroach) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [SCNA1_PERAM] Mediates the voltage-dependent sodium ion permeability of excitable membranes.[RuleBase:RU361132] [SCX2_ANDAU] Alpha toxins bind voltage-independently at site-3 of sodium channels (Nav) and inhibit the inactivation of the activated channels, thereby blocking neuronal transmission. This toxin is active against mammals. Publication Abstract from PubMed Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Nav channel alone and in complex with a lethal alpha-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of alpha-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Nav channels. Structural basis of alpha-scorpion toxin action on Nav channels.,Clairfeuille T, Cloake A, Infield DT, Llongueras JP, Arthur CP, Li ZR, Jian Y, Martin-Eauclaire MF, Bougis PE, Ciferri C, Ahern CA, Bosmans F, Hackos DH, Rohou A, Payandeh J Science. 2019 Mar 22;363(6433). pii: science.aav8573. doi:, 10.1126/science.aav8573. Epub 2019 Feb 7. PMID:30733386 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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