6n4q

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CryoEM structure of Nav1.7 VSD2 (actived state) in complex with the gating modifier toxin ProTx2CryoEM structure of Nav1.7 VSD2 (actived state) in complex with the gating modifier toxin ProTx2

Structural highlights

6n4q is a 12 chain structure with sequence from Human and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:Abu_1752 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TXPR2_THRPR] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable approximately 10 A translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists.

Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.,Xu H, Li T, Rohou A, Arthur CP, Tzakoniati F, Wong E, Estevez A, Kugel C, Franke Y, Chen J, Ciferri C, Hackos DH, Koth CM, Payandeh J Cell. 2019 Feb 7;176(4):702-715.e14. doi: 10.1016/j.cell.2018.12.018. Epub 2019, Jan 17. PMID:30661758[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222
  2. ↑ Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:http://dx.doi.org/10.1016/j.toxicon.2006.09.014
  3. ↑ Smith JJ, Cummins TR, Alphy S, Blumenthal KM. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. J Biol Chem. 2007 Apr 27;282(17):12687-97. Epub 2007 Mar 5. PMID:17339321 doi:http://dx.doi.org/10.1074/jbc.M610462200
  4. ↑ Sokolov S, Kraus RL, Scheuer T, Catterall WA. Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II. Mol Pharmacol. 2008 Mar;73(3):1020-8. Epub 2007 Dec 21. PMID:18156314 doi:http://dx.doi.org/10.1124/mol.107.041046
  5. ↑ Edgerton GB, Blumenthal KM, Hanck DA. Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5. Toxicon. 2008 Sep 1;52(3):489-500. Epub 2008 Jul 9. PMID:18657562 doi:http://dx.doi.org/S0041-0101(08)00401-7
  6. ↑ Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008 Nov;74(5):1476-84. doi: 10.1124/mol.108.047670. Epub 2008 Aug, 26. PMID:18728100 doi:http://dx.doi.org/10.1124/mol.108.047670
  7. ↑ Xu H, Li T, Rohou A, Arthur CP, Tzakoniati F, Wong E, Estevez A, Kugel C, Franke Y, Chen J, Ciferri C, Hackos DH, Koth CM, Payandeh J. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell. 2019 Feb 7;176(4):702-715.e14. doi: 10.1016/j.cell.2018.12.018. Epub 2019, Jan 17. PMID:30661758 doi:http://dx.doi.org/10.1016/j.cell.2018.12.018

6n4q, resolution 3.60Å

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