7xve: Difference between revisions

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-'''Unreleased structure'''
-The entry 7xve is ON HOLD
+==Human Nav1.7 mutant class-I==
+<StructureSection load='7xve' size='340' side='right'caption='[[7xve]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7xve]] 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=7XVE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XVE 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]] 2.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PW:(2S,3R,4E)-2-(ACETYLAMINO)-3-HYDROXYOCTADEC-4-EN-1-YL+DIHYDROGEN+PHOSPHATE'>1PW</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>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=7xve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xve OCA], [https://pdbe.org/7xve PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xve RCSB], [https://www.ebi.ac.uk/pdbsum/7xve PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xve 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Voltage-gated sodium (Na(v)) channel Na(v)1.7 has been targeted for the development of nonaddictive pain killers. Structures of Na(v)1.7 in distinct functional states will offer an advanced mechanistic understanding and aid drug discovery. Here we report the cryoelectron microscopy analysis of a human Na(v)1.7 variant that, with 11 rationally introduced point mutations, has a markedly right-shifted activation voltage curve with V(1/2) reaching 69 mV. The voltage-sensing domain in the first repeat (VSD(I)) in a 2.7-A resolution structure displays a completely down (deactivated) conformation. Compared to the structure of WT Na(v)1.7, three gating charge (GC) residues in VSD(I) are transferred to the cytosolic side through a combination of helix unwinding and spiral sliding of S4(I) and approximately 20 degrees domain rotation. A conserved WNcapital EF, Cyrilliccapital EF, CyrillicD motif on the cytoplasmic end of S3(I) stabilizes the down conformation of VSD(I). One GC residue is transferred in VSD(II) mainly through helix sliding. Accompanying GC transfer in VSD(I) and VSD(II), rearrangement and contraction of the intracellular gate is achieved through concerted movements of adjacent segments, including S4-5(I), S4-5(II), S5(II), and all S6 segments. Our studies provide important insight into the electromechanical coupling mechanism of the single-chain voltage-gated ion channels and afford molecular interpretations for a number of pain-associated mutations whose pathogenic mechanism cannot be revealed from previously reported Na(v) structures.
-Authors:
+Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Na(v)1.7.,Huang G, Wu Q, Li Z, Jin X, Huang X, Wu T, Pan X, Yan N Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2209164119. doi: , 10.1073/pnas.2209164119. Epub 2022 Jul 25. PMID:35878056<ref>PMID:35878056</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7xve" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Huang G]]
+[[Category: Li Z]]
+[[Category: Pan X]]
+[[Category: Wu Q]]
+[[Category: Yan N]]