6n4r

From Proteopedia

(Difference between revisions)

Current revision

CryoEM structure of Nav1.7 VSD2 (deactived state) in complex with the gating modifier toxin ProTx2

6n4r, resolution 4.20Å

Structural highlights

6n4r is a 12 chain structure with sequence from Aliarcobacter butzleri RM4018, Homo sapiens, Mus musculus and Thrixopelma pruriens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.2Å
Experimental data:	Check to display Experimental Data
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] A8EVM5_ALIB4

Publication Abstract from PubMed

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable approximately 10 A translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists.

Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.,Xu H, Li T, Rohou A, Arthur CP, Tzakoniati F, Wong E, Estevez A, Kugel C, Franke Y, Chen J, Ciferri C, Hackos DH, Koth CM, Payandeh J Cell. 2019 Feb 7;176(4):702-715.e14. doi: 10.1016/j.cell.2018.12.018. Epub 2019, Jan 17. PMID:30661758^[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
↑ Xu H, Li T, Rohou A, Arthur CP, Tzakoniati F, Wong E, Estevez A, Kugel C, Franke Y, Chen J, Ciferri C, Hackos DH, Koth CM, Payandeh J. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell. 2019 Feb 7;176(4):702-715.e14. doi: 10.1016/j.cell.2018.12.018. Epub 2019, Jan 17. PMID:30661758 doi:http://dx.doi.org/10.1016/j.cell.2018.12.018

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6n4r"

@@ Line 3: / Line 3: @@
 <SX load='6n4r' size='340' side='right' viewer='molstar' caption='[[6n4r]], [[Resolution|resolution]] 4.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6n4r]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N4R OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6N4R FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6n4r]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Aliarcobacter_butzleri_RM4018 Aliarcobacter butzleri RM4018], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Thrixopelma_pruriens Thrixopelma pruriens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N4R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N4R FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Abu_1752 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.2&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6n4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n4r OCA], [http://pdbe.org/6n4r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n4r RCSB], [http://www.ebi.ac.uk/pdbsum/6n4r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n4r ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6n4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n4r OCA], [https://pdbe.org/6n4r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n4r RCSB], [https://www.ebi.ac.uk/pdbsum/6n4r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n4r ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/SCN9A_HUMAN 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 ==
-[[http://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_THRPR]] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref>
+[https://www.uniprot.org/uniprot/SCN9A_HUMAN 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).<ref>PMID:15178348</ref> <ref>PMID:15385606</ref> <ref>PMID:16988069</ref> <ref>PMID:17145499</ref> <ref>PMID:17167479</ref> <ref>PMID:19369487</ref> <ref>PMID:24311784</ref> <ref>PMID:25240195</ref> <ref>PMID:26680203</ref> <ref>PMID:7720699</ref> [https://www.uniprot.org/uniprot/A8EVM5_ALIB4 A8EVM5_ALIB4]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 24: @@
 __TOC__
 </SX>
-[[Category: Human]]
+[[Category: Aliarcobacter butzleri RM4018]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Mus musculus]]
-[[Category: Arthur, C P]]
+[[Category: Thrixopelma pruriens]]
-[[Category: Ciferri, C]]
+[[Category: Arthur CP]]
-[[Category: Estevez, A]]
+[[Category: Ciferri C]]
-[[Category: Koth, C M]]
+[[Category: Estevez A]]
-[[Category: Payandeh, J]]
+[[Category: Koth CM]]
-[[Category: Rohou, A]]
+[[Category: Payandeh J]]
-[[Category: Xu, H]]
+[[Category: Rohou A]]
-[[Category: Gating modifier toxin]]
+[[Category: Xu H]]
-[[Category: Membrane protein]]
-[[Category: Voltage-gated sodium channel]]

6n4r

From Proteopedia

Current revision

CryoEM structure of Nav1.7 VSD2 (deactived state) in complex with the gating modifier toxin ProTx2

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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