2n8h

From Proteopedia

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Current revision

Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muOxi-GVIIJ

Structural highlights

2n8h is a 1 chain structure with sequence from Conus geographus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

O17J_CONGE Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin (GVIIJ(SSG)) blocks Nav1.1/SCN1A (Kd=11 nM), Nav1.2/SCN2A (Kd=11 nM), Nav1.3/SCN3A (Kd=15 nM), Nav1.4/SCN4A (Kd=4.7 nM), Nav1.6/SCN8A (Kd=360 nM) and Nav1.7/SCN9A (Kd=41 nM) (PubMed:24497506, PubMed:26039939). It binds the channel at the newly described site 8, which is composed by two surfaces whose one contains a non-disulfide-bonded cysteine (which is free to covalently bind the toxin Cys-71) (PubMed:24497506). It is noteworthy that coexpression of subunits beta-2 or beta-4 (but not beta-1 or beta-3) protects rNav1.1-1.7 against block by the toxin, since these subunits (thanks to their extracellular domain) covalently bind to the key cysteine of the channel, thus preventing the covalent binding of the toxin (PubMed:24497506, PubMed:25632083).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Cone snail toxins are well known blockers of voltage-gated sodium channels, a property that is of broad interest in biology and therapeutically in treating neuropathic pain and neurological disorders. Although most conotoxin channel blockers function by direct binding to a channel and disrupting its normal ion movement, conotoxin muO section sign-GVIIJ channel blocking is unique, using both favorable binding interactions with the channel and a direct tether via an intermolecular disulfide bond. Disulfide exchange is possible because conotoxin muO section sign-GVIIJ contains anS-cysteinylated Cys-24 residue that is capable of exchanging with a free cysteine thiol on the channel surface. Here, we present the solution structure of an analog of muO section sign-GVIIJ (GVIIJ[C24S]) and the results of structure-activity studies with synthetic muO section sign-GVIIJ variants. GVIIJ[C24S] adopts an inhibitor cystine knot structure, with two antiparallel beta-strands stabilized by three disulfide bridges. The loop region linking the beta-strands (loop 4) presents residue 24 in a configuration where it could bind to the proposed free cysteine of the channel (Cys-910, rat NaV1.2 numbering; at site 8). The structure-activity study shows that three residues (Lys-12, Arg-14, and Tyr-16) located in loop 2 and spatially close to residue 24 were also important for functional activity. We propose that the interaction of muO section sign-GVIIJ with the channel depends on not only disulfide tethering via Cys-24 to a free cysteine at site 8 on the channel but also the participation of key residues of muO section sign-GVIIJ on a distinct surface of the peptide.

Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin muO section sign-GVIIJ.,Green BR, Gajewiak J, Chhabra S, Skalicky JJ, Zhang MM, Rivier JE, Bulaj G, Olivera BM, Yoshikami D, Norton RS J Biol Chem. 2016 Mar 25;291(13):7205-20. doi: 10.1074/jbc.M115.697672. Epub 2016, Jan 27. PMID:26817840^[5]

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

References

↑ Gajewiak J, Azam L, Imperial J, Walewska A, Green BR, Bandyopadhyay PK, Raghuraman S, Ueberheide B, Bern M, Zhou HM, Minassian NA, Hagan RH, Flinspach M, Liu Y, Bulaj G, Wickenden AD, Olivera BM, Yoshikami D, Zhang MM. A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ. Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2758-63. PMID:24497506 doi:10.1073/pnas.1324189111
↑ Wilson MJ, Zhang MM, Gajewiak J, Azam L, Rivier JE, Olivera BM, Yoshikami D. Α μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ. J Neurophysiol. 2015 Apr 1;113(7):2289-301. PMID:25632083 doi:10.1152/jn.01004.2014
↑ Zhang MM, Gajewiak J, Azam L, Bulaj G, Olivera BM, Yoshikami D. Probing the Redox States of Sodium Channel Cysteines at the Binding Site of μO§-Conotoxin GVIIJ. Biochemistry. 2015 Jun 30;54(25):3911-20. PMID:26039939 doi:10.1021/acs.biochem.5b00390
↑ Green BR, Gajewiak J, Chhabra S, Skalicky JJ, Zhang MM, Rivier JE, Bulaj G, Olivera BM, Yoshikami D, Norton RS. Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin muO section sign-GVIIJ. J Biol Chem. 2016 Mar 25;291(13):7205-20. doi: 10.1074/jbc.M115.697672. Epub 2016, Jan 27. PMID:26817840 doi:http://dx.doi.org/10.1074/jbc.M115.697672
↑ Green BR, Gajewiak J, Chhabra S, Skalicky JJ, Zhang MM, Rivier JE, Bulaj G, Olivera BM, Yoshikami D, Norton RS. Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin muO section sign-GVIIJ. J Biol Chem. 2016 Mar 25;291(13):7205-20. doi: 10.1074/jbc.M115.697672. Epub 2016, Jan 27. PMID:26817840 doi:http://dx.doi.org/10.1074/jbc.M115.697672

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2n8h"

Categories: Conus geographus | Large Structures | Chhabra S | Green BR | Norton RS

@@ Line 1: / Line 1: @@
 ==Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muOxi-GVIIJ==
-<StructureSection load='2n8h' size='340' side='right'caption='[[2n8h]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2n8h' size='340' side='right'caption='[[2n8h]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2n8h]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N8H FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2n8h]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_geographus Conus geographus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N8H FirstGlance]. <br>
-</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</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=2n8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n8h OCA], [https://pdbe.org/2n8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n8h RCSB], [https://www.ebi.ac.uk/pdbsum/2n8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n8h ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/O17J_CONGE O17J_CONGE] Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin (GVIIJ(SSG)) blocks Nav1.1/SCN1A (Kd=11 nM), Nav1.2/SCN2A (Kd=11 nM), Nav1.3/SCN3A (Kd=15 nM), Nav1.4/SCN4A (Kd=4.7 nM), Nav1.6/SCN8A (Kd=360 nM) and Nav1.7/SCN9A (Kd=41 nM) (PubMed:24497506, PubMed:26039939). It binds the channel at the newly described site 8, which is composed by two surfaces whose one contains a non-disulfide-bonded cysteine (which is free to covalently bind the toxin Cys-71) (PubMed:24497506). It is noteworthy that coexpression of subunits beta-2 or beta-4 (but not beta-1 or beta-3) protects rNav1.1-1.7 against block by the toxin, since these subunits (thanks to their extracellular domain) covalently bind to the key cysteine of the channel, thus preventing the covalent binding of the toxin (PubMed:24497506, PubMed:25632083).<ref>PMID:24497506</ref> <ref>PMID:25632083</ref> <ref>PMID:26039939</ref> <ref>PMID:26817840</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Conus geographus]]
 [[Category: Large Structures]]
-[[Category: Chhabra, S]]
+[[Category: Chhabra S]]
-[[Category: Green, B R]]
+[[Category: Green BR]]
-[[Category: Norton, R S]]
+[[Category: Norton RS]]
-[[Category: Inhibitor cysteine knot]]
-[[Category: Toxin]]

2n8h

From Proteopedia

Current revision

Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muOxi-GVIIJ

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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