7wfr

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Current revision (06:53, 21 November 2024) (edit) (undo)
 
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==sodium channel III==
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==Human Nav1.8 with A-803467, class III==
<StructureSection load='7wfr' size='340' side='right'caption='[[7wfr]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
<StructureSection load='7wfr' size='340' side='right'caption='[[7wfr]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7wfr]] 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=7WFR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WFR FirstGlance]. <br>
<table><tr><td colspan='2'>[[7wfr]] 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=7WFR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WFR FirstGlance]. <br>
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</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
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<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=7wfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wfr OCA], [https://pdbe.org/7wfr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wfr RCSB], [https://www.ebi.ac.uk/pdbsum/7wfr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wfr 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=7wfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wfr OCA], [https://pdbe.org/7wfr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wfr RCSB], [https://www.ebi.ac.uk/pdbsum/7wfr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wfr ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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.
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[https://www.uniprot.org/uniprot/SCNAA_HUMAN SCNAA_HUMAN] Brugada syndrome;Primary erythromelalgia;Hereditary sodium channelopathy-related small fibers neuropathy;Paroxysmal extreme pain disorder;Romano-Ward syndrome;Congenital insensitivity to pain-anosmia-neuropathic arthropathy. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
== Function ==
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[[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>
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[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:23115331</ref> <ref>PMID:9839820</ref>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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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.
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The dorsal root ganglia-localized voltage-gated sodium (Na(v)) channel Na(v)1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na(v)1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na(v)1.8 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 (VSD(I)) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD(I) 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 S6(IV). Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6(I) and Gly1406 on S6(III), allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Na(v) channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics.
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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>
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Structural basis for high-voltage activation and subtype-specific inhibition of human Na(v)1.8.,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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 7wfr" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 7wfr" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
== References ==
<references/>
<references/>

Current revision

Human Nav1.8 with A-803467, class III

PDB ID 7wfr

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