View source for 7w77


==cryo-EM structure of human NaV1.3/beta1/beta2-bulleyaconitineA==
<StructureSection load='7w77' size='340' side='right'caption='[[7w77]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7w77]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W77 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W77 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]] 3.3&#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=9Z9:(1~{S},2~{S},4~{S},5~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-16-[4-methoxy-3-(methoxymethyl)butoxy]-5,7,9,13-tetramethyl-spiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2-oxane]'>9Z9</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</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=7w77 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w77 OCA], [https://pdbe.org/7w77 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w77 RCSB], [https://www.ebi.ac.uk/pdbsum/7w77 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w77 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SCN1B_HUMAN 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.
== Function ==
[https://www.uniprot.org/uniprot/SCN1B_HUMAN 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.<ref>PMID:14622265</ref>   Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.<ref>PMID:14622265</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Voltage-gated sodium (Na(V)) channels play fundamental roles in initiating and propagating action potentials. Na(V)1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na(V)1.3/beta1/beta2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na(V) channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na(V) channels and pave a way for subtype-selective therapeutic development.

Structural basis for modulation of human Na(V)1.3 by clinical drug and selective antagonist.,Li X, Xu F, Xu H, Zhang S, Gao Y, Zhang H, Dong Y, Zheng Y, Yang B, Sun J, Zhang XC, Zhao Y, Jiang D Nat Commun. 2022 Mar 11;13(1):1286. doi: 10.1038/s41467-022-28808-5. PMID:35277491<ref>PMID:35277491</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7w77" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jiang D]]
[[Category: Li X]]