2n8h
From Proteopedia
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==Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muOxi-GVIIJ== | ==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]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | ||
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2n8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n8h OCA], [http://pdbe.org/2n8h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n8h RCSB], [http://www.ebi.ac.uk/pdbsum/2n8h PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2n8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n8h OCA], [http://pdbe.org/2n8h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n8h RCSB], [http://www.ebi.ac.uk/pdbsum/2n8h PDBsum]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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. | ||
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| + | 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<ref>PMID:26817840</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 2n8h" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 16:43, 10 May 2016
Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muOxi-GVIIJ
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