7xvf

From Proteopedia

(Difference between revisions)

Current revision

Nav1.7 mutant class2

Structural highlights

7xvf is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.8Å
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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

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).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

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.

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^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H, Nagase T, Nakajima T. Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A. FEBS Lett. 2004 Jun 4;567(2-3):339-43. PMID:15178348 doi:http://dx.doi.org/10.1016/j.febslet.2004.04.092
↑ Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci. 2004 Sep 22;24(38):8232-6. PMID:15385606 doi:http://dx.doi.org/10.1523/JNEUROSCI.2695-04.2004
↑ Choi JS, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006 Nov 14;67(9):1563-7. doi: 10.1212/01.wnl.0000231514.33603.1e., Epub 2006 Sep 20. PMID:16988069 doi:http://dx.doi.org/10.1212/01.wnl.0000231514.33603.1e
↑ Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006 Dec 7;52(5):767-74. doi: 10.1016/j.neuron.2006.10.006. PMID:17145499 doi:http://dx.doi.org/10.1016/j.neuron.2006.10.006
↑ Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8. PMID:17167479 doi:http://dx.doi.org/nature05413
↑ Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, Cao X, Yang Y, Waxman SG. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain. 2009 Jul;132(Pt 7):1711-22. doi: 10.1093/brain/awp078. Epub 2009 Apr 15. PMID:19369487 doi:http://dx.doi.org/10.1093/brain/awp078
↑ Eberhardt M, Nakajima J, Klinger AB, Neacsu C, Huhne K, O'Reilly AO, Kist AM, Lampe AK, Fischer K, Gibson J, Nau C, Winterpacht A, Lampert A. Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation. J Biol Chem. 2014 Jan 24;289(4):1971-80. doi: 10.1074/jbc.M113.502211. Epub 2013 , Dec 5. PMID:24311784 doi:http://dx.doi.org/10.1074/jbc.M113.502211
↑ Tan ZY, Priest BT, Krajewski JL, Knopp KL, Nisenbaum ES, Cummins TR. Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker. FEBS Lett. 2014 Nov 3;588(21):3964-9. doi: 10.1016/j.febslet.2014.09.011. Epub, 2014 Sep 19. PMID:25240195 doi:http://dx.doi.org/10.1016/j.febslet.2014.09.011
↑ Ahuja S, Mukund S, Deng L, Khakh K, Chang E, Ho H, Shriver S, Young C, Lin S, Johnson JP Jr, Wu P, Li J, Coons M, Tam C, Brillantes B, Sampang H, Mortara K, Bowman KK, Clark KR, Estevez A, Xie Z, Verschoof H, Grimwood M, Dehnhardt C, Andrez JC, Focken T, Sutherlin DP, Safina BS, Starovasnik MA, Ortwine DF, Franke Y, Cohen CJ, Hackos DH, Koth CM, Payandeh J. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464. PMID:26680203 doi:http://dx.doi.org/10.1126/science.aac5464
↑ Klugbauer N, Lacinova L, Flockerzi V, Hofmann F. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 1995 Mar 15;14(6):1084-90. PMID:7720699
↑ Huang G, Wu Q, Li Z, Jin X, Huang X, Wu T, Pan X, Yan N. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Na(v)1.7. Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2209164119. PMID:35878056 doi:10.1073/pnas.2209164119

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7xvf"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7xvf]] 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=7XVF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XVF FirstGlance]. <br>
-</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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.8&#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=7xvf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xvf OCA], [https://pdbe.org/7xvf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xvf RCSB], [https://www.ebi.ac.uk/pdbsum/7xvf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xvf ProSAT]</span></td></tr>
 </table>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 7xvf" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ion channels 3D structures|Ion channels 3D structures]]
 == References ==
 <references/>

7xvf

From Proteopedia

Current revision

Nav1.7 mutant class2

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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