View source for 7xm9


==Cryo-EM structure of human NaV1.7/beta1/beta2-XEN907==
<StructureSection load='7xm9' size='340' side='right'caption='[[7xm9]], [[Resolution|resolution]] 3.22&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xm9]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Aequorea_victoria Aequorea victoria] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XM9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XM9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.22&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6OU:[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl]+(~{Z})-octadec-9-enoate'>6OU</scene>, <scene name='pdbligand=G2E:(7~{R})-1-pentylspiro[6~{H}-furo[3,2-f][1,3]benzodioxole-7,3-indole]-2-one'>G2E</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=7xm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xm9 OCA], [https://pdbe.org/7xm9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xm9 RCSB], [https://www.ebi.ac.uk/pdbsum/7xm9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xm9 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 ==
[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> 
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== Publication Abstract from PubMed ==
Voltage-gated sodium channel Na(V)1.7 plays essential roles in pain and odor perception. Na(V)1.7 variants cause pain disorders. Accordingly, Na(V)1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na(V)1.7/beta1/beta2 complexed with inhibitors XEN907, TC-N1752 and Na(V)1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes alpha- to pi-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces pi-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na(V)1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na(V)1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na(V)1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics.

Structural basis for Na(V)1.7 inhibition by pore blockers.,Zhang J, Shi Y, Huang Z, Li Y, Yang B, Gong J, Jiang D Nat Struct Mol Biol. 2022 Dec;29(12):1208-1216. doi: 10.1038/s41594-022-00860-1. , Epub 2022 Nov 24. PMID:36424527<ref>PMID:36424527</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7xm9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Aequorea victoria]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jiang DH]]
[[Category: Zhang JT]]