| Structural highlights
8g1a is a 3 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 2.8Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
SCN9A_HUMAN Channelopathy-associated congenital insensitivity to pain;Dravet syndrome;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Generalized epilepsy with febrile seizures-plus;Hereditary sensory and autonomic neuropathy type 2;Paroxysmal extreme pain disorder;Erythromelalgia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
SCN9A_HUMAN 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 Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Na(v)1.7 channels at sub-micromolar concentrations in a state-dependent manner. Electrophysiological experiments show that CBD binds to the inactivated state of Na(v)1.7 channels with a dissociation constant of about 50 nM. The cryo-EM structure of CBD bound to Na(v)1.7 channels reveals two distinct binding sites. One is in the IV-I fenestration near the upper pore. The other binding site is directly next to the inactivated "wedged" position of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, which mediates fast inactivation. Consistent with producing a direct stabilization of the inactivated state, mutating residues in this binding site greatly reduced state-dependent binding of CBD. The identification of this binding site may enable design of compounds with improved properties compared to CBD itself.
Cannabidiol inhibits Na(v) channels through two distinct binding sites.,Huang J, Fan X, Jin X, Jo S, Zhang HB, Fujita A, Bean BP, Yan N Nat Commun. 2023 Jun 17;14(1):3613. doi: 10.1038/s41467-023-39307-6. PMID:37330538[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H, Nagase T, Nakajima T. Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A. FEBS Lett. 2004 Jun 4;567(2-3):339-43. PMID:15178348 doi:http://dx.doi.org/10.1016/j.febslet.2004.04.092
- ↑ Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci. 2004 Sep 22;24(38):8232-6. PMID:15385606 doi:http://dx.doi.org/10.1523/JNEUROSCI.2695-04.2004
- ↑ Choi JS, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006 Nov 14;67(9):1563-7. doi: 10.1212/01.wnl.0000231514.33603.1e., Epub 2006 Sep 20. PMID:16988069 doi:http://dx.doi.org/10.1212/01.wnl.0000231514.33603.1e
- ↑ Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006 Dec 7;52(5):767-74. doi: 10.1016/j.neuron.2006.10.006. PMID:17145499 doi:http://dx.doi.org/10.1016/j.neuron.2006.10.006
- ↑ Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8. PMID:17167479 doi:http://dx.doi.org/nature05413
- ↑ Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, Cao X, Yang Y, Waxman SG. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain. 2009 Jul;132(Pt 7):1711-22. doi: 10.1093/brain/awp078. Epub 2009 Apr 15. PMID:19369487 doi:http://dx.doi.org/10.1093/brain/awp078
- ↑ Eberhardt M, Nakajima J, Klinger AB, Neacsu C, Huhne K, O'Reilly AO, Kist AM, Lampe AK, Fischer K, Gibson J, Nau C, Winterpacht A, Lampert A. Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation. J Biol Chem. 2014 Jan 24;289(4):1971-80. doi: 10.1074/jbc.M113.502211. Epub 2013 , Dec 5. PMID:24311784 doi:http://dx.doi.org/10.1074/jbc.M113.502211
- ↑ Tan ZY, Priest BT, Krajewski JL, Knopp KL, Nisenbaum ES, Cummins TR. Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker. FEBS Lett. 2014 Nov 3;588(21):3964-9. doi: 10.1016/j.febslet.2014.09.011. Epub, 2014 Sep 19. PMID:25240195 doi:http://dx.doi.org/10.1016/j.febslet.2014.09.011
- ↑ Ahuja S, Mukund S, Deng L, Khakh K, Chang E, Ho H, Shriver S, Young C, Lin S, Johnson JP Jr, Wu P, Li J, Coons M, Tam C, Brillantes B, Sampang H, Mortara K, Bowman KK, Clark KR, Estevez A, Xie Z, Verschoof H, Grimwood M, Dehnhardt C, Andrez JC, Focken T, Sutherlin DP, Safina BS, Starovasnik MA, Ortwine DF, Franke Y, Cohen CJ, Hackos DH, Koth CM, Payandeh J. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464. PMID:26680203 doi:http://dx.doi.org/10.1126/science.aac5464
- ↑ Klugbauer N, Lacinova L, Flockerzi V, Hofmann F. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 1995 Mar 15;14(6):1084-90. PMID:7720699
- ↑ Huang J, Fan X, Jin X, Jo S, Zhang HB, Fujita A, Bean BP, Yan N. Cannabidiol inhibits Na(v) channels through two distinct binding sites. Nat Commun. 2023 Jun 17;14(1):3613. PMID:37330538 doi:10.1038/s41467-023-39307-6
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