Structural highlights
7wel 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.
|
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[SCNAA_HUMAN] Congenital insensitivity to pain-anosmia-neuropathic arthropathy;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Brugada syndrome;Paroxysmal extreme pain disorder;Romano-Ward syndrome. 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]
Publication Abstract from PubMed
The dorsal root ganglia-localized voltage-gated sodium (Nav) channel Nav1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Nav1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Nav1.8 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 (VSDI) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSDI 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 S6IV. Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6I and Gly1406 on S6III, allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Nav 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 Nav1.8.,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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
