8fhd

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Cryo-EM structure of human voltage-gated sodium channel Nav1.6

Structural highlights

8fhd is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:9Z9, BMA, CLR, LPE, MAN, NAG, P3X, P5S, PCW, Y01
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SCN8A_HUMAN Non-specific early-onset epileptic encephalopathy;Infantile convulsions and choreoathetosis;Benign familial infantile epilepsy. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease may be caused by variants affecting the gene represented in this entry.

Function

SCN8A_HUMAN Mediates the voltage-dependent sodium ion permeability of excitable membranes (PubMed:29726066). Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.[1] [2] [3] In macrophages and melanoma cells, may participate in the control of podosome and invadopodia formation.[4]

Publication Abstract from PubMed

Voltage-gated sodium channel Na(v)1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na(v)1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na(v)1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na(v)1.6 in the presence of auxiliary subunits beta1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 A. The overall structure represents an inactivated state with closed pore domain (PD) and all "up" voltage-sensing domains. A conserved carbohydrate-aromatic interaction involving Trp302 and Asn326, together with the beta1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na(v)1.6-specific blockers. Structural mapping of disease-related Na(v)1.6 mutations provides insights into their pathogenic mechanism.

Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6.,Fan X, Huang J, Jin X, Yan N Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2220578120. doi: , 10.1073/pnas.2220578120. Epub 2023 Jan 25. PMID:36696443[5]

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

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References

  1. ↑ Carrithers MD, Chatterjee G, Carrithers LM, Offoha R, Iheagwara U, Rahner C, Graham M, Waxman SG. Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A. J Biol Chem. 2009 Mar 20;284(12):8114-26. PMID:19136557 doi:10.1074/jbc.M801892200
  2. ↑ Wagnon JL, Mencacci NE, Barker BS, Wengert ER, Bhatia KP, Balint B, Carecchio M, Wood NW, Patel MK, Meisler MH. Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Hum Mutat. 2018 Jul;39(7):965-969. PMID:29726066 doi:10.1002/humu.23547
  3. ↑ Fry AE, Marra C, Derrick AV, Pickrell WO, Higgins AT, Te Water Naude J, McClatchey MA, Davies SJ, Metcalfe KA, Tan HJ, Mohanraj R, Avula S, Williams D, Brady LI, Mesterman R, Tarnopolsky MA, Zhang Y, Yang Y, Wang X, Rees MI, Goldfarb M, Chung SK. Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy. Am J Hum Genet. 2021 Jan 7;108(1):176-185. PMID:33245860 doi:10.1016/j.ajhg.2020.10.017
  4. ↑ Wagnon JL, Mencacci NE, Barker BS, Wengert ER, Bhatia KP, Balint B, Carecchio M, Wood NW, Patel MK, Meisler MH. Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Hum Mutat. 2018 Jul;39(7):965-969. PMID:29726066 doi:10.1002/humu.23547
  5. ↑ Fan X, Huang J, Jin X, Yan N. Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6. Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2220578120. PMID:36696443 doi:10.1073/pnas.2220578120

Contents


PDB ID 8fhd

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