View source for 2lxg


==NMR solution structure of Mu-conotoxin KIIIA==
<StructureSection load='2lxg' size='340' side='right'caption='[[2lxg]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2lxg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_kinoshitai Conus kinoshitai]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LXG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LXG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=2lxg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lxg OCA], [https://pdbe.org/2lxg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lxg RCSB], [https://www.ebi.ac.uk/pdbsum/2lxg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lxg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CM3A_CONKI CM3A_CONKI] Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.2/SCN2A and rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.3/SCN3A, rNav1.5/SCN5A, mNav1.6/SCN8A, and rNav1.7/SCN9A. On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of SCN9A is modified when beta-subunits are coexpressed with the alpha subunit. Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits).<ref>PMID:15882064</ref> <ref>PMID:17724025</ref> <ref>PMID:18950653</ref> <ref>PMID:21652775</ref> <ref>PMID:21709136</ref> <ref>PMID:21781281</ref> <ref>PMID:23146020</ref> 
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== Publication Abstract from PubMed ==
In the preparation of synthetic conotoxins containing multiple disulfide bonds, oxidative folding can produce numerous permutations of disulfide bond connectivities. Establishing the native disulfide connectivities thus presents a significant challenge when the venom-derived peptide is not available, as is increasingly the case when conotoxins are identified from cDNA sequences. Here, we investigate the disulfide connectivity of mu-conotoxin KIIIA, which was predicted originally to have a [C1-C9,C2-C15,C4-C16] disulfide pattern based on homology with closely related mu-conotoxins. The two major isomers of synthetic mu-KIIIA formed during oxidative folding were purified and their disulfide connectivities mapped by direct mass spectrometric collision-induced dissociation fragmentation of the disulfide-bonded polypeptides. Our results show that the major oxidative folding product adopts a [C1-C15,C2-C9,C4-C16] disulfide connectivity, while the minor product adopts a [C1-C16,C2-C9,C4-C15] connectivity. Both of these peptides were potent blockers of Na(V)1.2 (K(d) values of 5 and 230 nM, respectively). The solution structure for mu-KIIIA based on nuclear magnetic resonance data was recalculated with the [C1-C15,C2-C9,C4-C16] disulfide pattern; its structure was very similar to the mu-KIIIA structure calculated with the incorrect [C1-C9,C2-C15,C4-C16] disulfide pattern, with an alpha-helix spanning residues 7-12. In addition, the major folding isomers of mu-KIIIB, an N-terminally extended isoform of mu-KIIIA identified from its cDNA sequence, were isolated. These folding products had the same disulfide connectivities as mu-KIIIA, and both blocked Na(V)1.2 (K(d) values of 470 and 26 nM, respectively). Our results establish that the preferred disulfide pattern of synthetic mu-KIIIA and mu-KIIIB folded in vitro is 1-5/2-4/3-6 but that other disulfide isomers are also potent sodium channel blockers. These findings raise questions about the disulfide pattern(s) of mu-KIIIA in the venom of Conus kinoshitai; indeed, the presence of multiple disulfide isomers in the venom could provide a means of further expanding the snail's repertoire of active peptides.

Distinct Disulfide Isomers of mu-Conotoxins KIIIA and KIIIB Block Voltage-Gated Sodium Channels.,Khoo KK, Gupta K, Green BR, Zhang MM, Watkins M, Olivera BM, Balaram P, Yoshikami D, Bulaj G, Norton RS Biochemistry. 2012 Nov 28. PMID:23167564<ref>PMID:23167564</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Conus kinoshitai]]
[[Category: Large Structures]]
[[Category: Khoo KK]]
[[Category: Norton RS]]