7we4

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Human Nav1.8 with A-803467, class I

Structural highlights

7we4 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 2.7Å
Ligands:95T, CLR, LPE, NAG, P5S, PCW
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

The dorsal root ganglia-localized voltage-gated sodium (Na(v)) channel Na(v)1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na(v)1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na(v)1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 A. The first voltage-sensing domain (VSD(I)) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD(I) and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavity of the PD, clenching S6(IV). Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6(I) and Gly1406 on S6(III), allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Na(v) channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics.

Structural basis for high-voltage activation and subtype-specific inhibition of human Na(v)1.8.,Huang X, Jin X, Huang G, Huang J, Wu T, Li Z, Chen J, Kong F, Pan X, Yan N Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119. doi: , 10.1073/pnas.2208211119. Epub 2022 Jul 19. PMID:35858452[3]

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

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Citations
3 reviews cite this structure
Insights into the voltage-gated sodium channel, Na<sub>V</sub>1.8, and its role in visceral pain perception.
Heinle et al. (2024)
2 more
18 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Huang X, Jin X, Huang G, Huang J, Wu T, Li Z, Chen J, Kong F, Pan X, Yan N. Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8. Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119. doi:, 10.1073/pnas.2208211119. Epub 2022 Jul 19. PMID:35858452 doi:http://dx.doi.org/10.1073/pnas.2208211119

Contents


PDB ID 7we4

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OCA

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