7we4: Difference between revisions
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==sodium channel I== | ==sodium channel I== | ||
<StructureSection load='7we4' size='340' side='right'caption='[[7we4]]' scene=''> | <StructureSection load='7we4' size='340' side='right'caption='[[7we4]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WE4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7we4]] is a 1 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=7WE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WE4 FirstGlance]. <br> | ||
</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=7we4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7we4 OCA], [https://pdbe.org/7we4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7we4 RCSB], [https://www.ebi.ac.uk/pdbsum/7we4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7we4 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=95T:5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide'>95T</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=LPE:1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>LPE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P5S:O-[(R)-{[(2R)-2,3-BIS(OCTADECANOYLOXY)PROPYL]OXY}(HYDROXY)PHOSPHORYL]-L-SERINE'>P5S</scene>, <scene name='pdbligand=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</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=7we4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7we4 OCA], [https://pdbe.org/7we4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7we4 RCSB], [https://www.ebi.ac.uk/pdbsum/7we4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7we4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/SCNAA_HUMAN SCNAA_HUMAN]] Congenital insensitivity to pain-anosmia-neuropathic arthropathy;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Brugada syndrome;Paroxysmal extreme pain disorder;Romano-Ward syndrome. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/SCNAA_HUMAN SCNAA_HUMAN]] Tetrodotoxin-resistant channel that 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 sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.<ref>PMID:9839820</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The dorsal root ganglia-localized voltage-gated sodium (Nav) channel Nav1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Nav1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Nav1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 A. The first voltage-sensing domain (VSDI) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSDI and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavity of the PD, clenching S6IV. Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6I and Gly1406 on S6III, allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Nav channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics. | |||
Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8.,Huang X, Jin X, Huang G, Huang J, Wu T, Li Z, Chen J, Kong F, Pan X, Yan N Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119. doi:, 10.1073/pnas.2208211119. Epub 2022 Jul 19. PMID:35858452<ref>PMID:35858452</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7we4" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Huang GX]] | [[Category: Huang GX]] | ||
