| Structural highlights
9dbk is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 3.12Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
SCNAA_HUMAN Brugada syndrome;Primary erythromelalgia;Hereditary sodium channelopathy-related small fibers neuropathy;Paroxysmal extreme pain disorder;Romano-Ward syndrome;Congenital insensitivity to pain-anosmia-neuropathic arthropathy. The disease is caused by variants affecting the gene represented in this entry.
Function
SCNAA_HUMAN Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.[1] [2]
Publication Abstract from PubMed
Voltage-gated sodium channels (Na(V)s) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human Na(V) isoforms, Na(V)1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-Na(V)1.8 and the Protoxin-I-bound complex at 3.1 A and 2.8 A resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSD(I) was unresolvable. We find that Protoxin-I binds to and displaces the VSD(II) S3-S4 linker, hindering translocation of the S4(II) helix during activation.
Structural basis of inhibition of human Na(V)1.8 by the tarantula venom peptide Protoxin-I.,Neumann B, McCarthy S, Gonen S Nat Commun. 2025 Feb 7;16(1):1459. doi: 10.1038/s41467-024-55764-z. PMID:39920100[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19444-9. PMID:23115331 doi:10.1073/pnas.1216080109
- ↑ Rabert DK, Koch BD, Ilnicka M, Obernolte RA, Naylor SL, Herman RC, Eglen RM, Hunter JC, Sangameswaran L. A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A. Pain. 1998 Nov;78(2):107-114. doi: 10.1016/S0304-3959(98)00120-1. PMID:9839820 doi:http://dx.doi.org/10.1016/S0304-3959(98)00120-1
- ↑ Neumann B, McCarthy S, Gonen S. Structural basis of inhibition of human Na(V)1.8 by the tarantula venom peptide Protoxin-I. Nat Commun. 2025 Feb 7;16(1):1459. PMID:39920100 doi:10.1038/s41467-024-55764-z
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