| Structural highlights
6j8i is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | SCN2B, UNQ326/PRO386 (HUMAN), SCN9A, NENA (HUMAN), SCN1B (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[SCN2B_HUMAN] Familial atrial fibrillation. The disease is caused by mutations affecting the gene represented in this entry. Genetic variations in SCN2B may be involved in Brugada syndrome (PubMed:23559163). This tachyarrhythmia is characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset.[1] [SCN1B_HUMAN] Dravet syndrome;Familial progressive cardiac conduction defect;Generalized epilepsy with febrile seizures-plus;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis. 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. [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
[SCN2B_HUMAN] Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-2 causes an increase in the plasma membrane surface area and in its folding into microvilli. Interacts with TNR may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier (By similarity). [SCN1B_HUMAN] Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.[2] Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.[3] [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).[4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. Here we report the cryo-EM structures of the human Nav1.7-beta1-beta2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with Protoxin-II and saxitoxin with Huwentoxin-IV, both determined at overall resolutions of 3.2 A. The two structures are nearly identical except for minor shifts of VSDII, whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional Protoxin-II sits on top of the S3-S4 linker in VSDIV The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Nav1.7 and establish the foundation for structure-aided development of analgesics.
Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins.,Shen H, Liu D, Wu K, Lei J, Yan N Science. 2019 Feb 14. pii: science.aaw2493. doi: 10.1126/science.aaw2493. PMID:30765606[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Riuro H, Beltran-Alvarez P, Tarradas A, Selga E, Campuzano O, Verges M, Pagans S, Iglesias A, Brugada J, Brugada P, Vazquez FM, Perez GJ, Scornik FS, Brugada R. A missense mutation in the sodium channel beta2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum Mutat. 2013 Jul;34(7):961-6. doi: 10.1002/humu.22328. Epub 2013 Apr 29. PMID:23559163 doi:http://dx.doi.org/10.1002/humu.22328
- ↑ Qin N, D'Andrea MR, Lubin ML, Shafaee N, Codd EE, Correa AM. Molecular cloning and functional expression of the human sodium channel beta1B subunit, a novel splicing variant of the beta1 subunit. Eur J Biochem. 2003 Dec;270(23):4762-70. PMID:14622265
- ↑ Qin N, D'Andrea MR, Lubin ML, Shafaee N, Codd EE, Correa AM. Molecular cloning and functional expression of the human sodium channel beta1B subunit, a novel splicing variant of the beta1 subunit. Eur J Biochem. 2003 Dec;270(23):4762-70. PMID:14622265
- ↑ 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
- ↑ Shen H, Liu D, Wu K, Lei J, Yan N. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science. 2019 Feb 14. pii: science.aaw2493. doi: 10.1126/science.aaw2493. PMID:30765606 doi:http://dx.doi.org/10.1126/science.aaw2493
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