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1q2j

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Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA

Structural highlights

1q2j is a 1 chain structure with sequence from Conus stercusmuscarum. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CM3A_CONSE Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin blocks rNav1.5/SCN5A (IC(50) is 1.3 uM), rNav1.6/SCN8A (IC(50) is 160 nM), rNav1.7/SCN9A (IC(50) is 1.3 uM), rNav1.1/SCN1A (K(d) is 3.8 nM), rNav1.2/SCN2A (K(d) is 1.3 nM), rNav1.4/SCN4A (K(d) is 0.22 nM), rNav1.6/SCN8A (K(d) is 69 nM), and rNav1.7/SCN9A (K(d) is 260 nM). This toxin is very potent but weakly discriminating among sodium channels. The block of these channels is modified when beta-subunits are coexpressed with alpha subunits. 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).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

SmIIIA is a new micro-conotoxin isolated recently from Conus stercusmuscarum. Although it shares several biochemical characteristics with other micro-conotoxins (the arrangement of cysteine residues and a conserved arginine believed to interact with residues near the channel pore), it has several distinctive features, including the absence of hydroxyproline, and is the first specific antagonist of tetrodotoxin-resistant voltage-gated sodium channels to be characterized. It therefore represents a potentially useful tool to investigate the functional roles of these channels. We have determined the three-dimensional structure of SmIIIA in aqueous solution. Consistent with the absence of hydroxyprolines, SmIIIA adopts a single conformation with all peptide bonds in the trans configuration. The spatial orientations of several conserved Arg and Lys side chains, including Arg14 (using a consensus numbering system), which plays a key role in sodium channel binding, are similar to those in other micro-conotoxins but the N-terminal regions differ, reflecting the trans conformation for the peptide bond preceding residue 8 in SmIIIA, as opposed to the cis conformation in micro-conotoxins GIIIA and GIIIB. Comparison of the surfaces of SmIIIA with other micro-conotoxins suggests that the affinity of SmIIIA for TTX-resistant channels is influenced by the Trp15 side chain, which is unique to SmIIIA. Arg17, which replaces Lys in the other micro-conotoxins, may also be important. Consistent with these inferences from the structure, assays of two chimeras of SmIIIA and PIIIA in which their N- and C-terminal halves were recombined, indicated that residues in the C-terminal half of SmIIIA confer affinity for tetrodotoxin-resistant sodium channels in the cell bodies of frog sympathetic neurons. SmIIIA and the chimera possessing the C-terminal half of SmIIIA also inhibit tetrodotoxin-resistant sodium channels in the postganglionic axons of sympathetic neurons, as indicated by their inhibition of C-neuron compound action potentials that persist in the presence of tetrodotoxin.

Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA.,Keizer DW, West PJ, Lee EF, Yoshikami D, Olivera BM, Bulaj G, Norton RS J Biol Chem. 2003 Nov 21;278(47):46805-13. Epub 2003 Sep 10. PMID:12970353^[5]

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

References

↑ West PJ, Bulaj G, Garrett JE, Olivera BM, Yoshikami D. Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons. Biochemistry. 2002 Dec 24;41(51):15388-93. doi: 10.1021/bi0265628. PMID:12484778 doi:http://dx.doi.org/10.1021/bi0265628
↑ Wilson MJ, Yoshikami D, Azam L, Gajewiak J, Olivera BM, Bulaj G, Zhang MM. mu-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10302-7. doi:, 10.1073/pnas.1107027108. Epub 2011 Jun 7. PMID:21652775 doi:http://dx.doi.org/10.1073/pnas.1107027108
↑ Favreau P, Benoit E, Hocking HG, Carlier L, D'hoedt D, Leipold E, Markgraf R, Schlumberger S, Cordova MA, Gaertner H, Paolini-Bertrand M, Hartley O, Tytgat J, Heinemann SH, Bertrand D, Boelens R, Stocklin R, Molgo J. Pharmacological characterization of a novel mu-conopeptide, CnIIIC, indicates potent and preferential inhibition of sodium channel subtypes (Na(V) 1.2/1.4) and reveals unusual activity on neuronal nicotinic acetylcholine receptors. Br J Pharmacol. 2012 Jan 9. doi: 10.1111/j.1476-5381.2012.01837.x. PMID:22229737 doi:10.1111/j.1476-5381.2012.01837.x
↑ Zhang MM, Wilson MJ, Azam L, Gajewiak J, Rivier JE, Bulaj G, Olivera BM, Yoshikami D. Co-expression of Na(V)beta subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking mu-conotoxins. Br J Pharmacol. 2013 Apr;168(7):1597-610. doi: 10.1111/bph.12051. PMID:23146020 doi:http://dx.doi.org/10.1111/bph.12051
↑ Keizer DW, West PJ, Lee EF, Yoshikami D, Olivera BM, Bulaj G, Norton RS. Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA. J Biol Chem. 2003 Nov 21;278(47):46805-13. Epub 2003 Sep 10. PMID:12970353 doi:http://dx.doi.org/10.1074/jbc.M309222200

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/1q2j"

@@ Line 1: / Line 1: @@
 ==Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA==
-<StructureSection load='1q2j' size='340' side='right' caption='[[1q2j]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='1q2j' size='340' side='right'caption='[[1q2j]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1q2j]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q2J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1Q2J FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1q2j]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_stercusmuscarum Conus stercusmuscarum]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Q2J FirstGlance]. <br>
-</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=1q2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q2j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1q2j RCSB], [http://www.ebi.ac.uk/pdbsum/1q2j PDBsum]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=1q2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q2j OCA], [https://pdbe.org/1q2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1q2j RCSB], [https://www.ebi.ac.uk/pdbsum/1q2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1q2j ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/CM3A_CONSE CM3A_CONSE] Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin blocks rNav1.5/SCN5A (IC(50) is 1.3 uM), rNav1.6/SCN8A (IC(50) is 160 nM), rNav1.7/SCN9A (IC(50) is 1.3 uM), rNav1.1/SCN1A (K(d) is 3.8 nM), rNav1.2/SCN2A (K(d) is 1.3 nM), rNav1.4/SCN4A (K(d) is 0.22 nM), rNav1.6/SCN8A (K(d) is 69 nM), and rNav1.7/SCN9A (K(d) is 260 nM). This toxin is very potent but weakly discriminating among sodium channels. The block of these channels is modified when beta-subunits are coexpressed with alpha subunits. 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:12484778</ref> <ref>PMID:21652775</ref> <ref>PMID:22229737</ref> <ref>PMID:23146020</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 14: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1q2j" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Bulaj, G.]]
+[[Category: Conus stercusmuscarum]]
-[[Category: Keizer, D W.]]
+[[Category: Large Structures]]
-[[Category: Lee, E F.]]
+[[Category: Bulaj G]]
-[[Category: Norton, R S.]]
+[[Category: Keizer DW]]
-[[Category: Olivera, B M.]]
+[[Category: Lee EF]]
-[[Category: West, P J.]]
+[[Category: Norton RS]]
-[[Category: Yoshikami, D.]]
+[[Category: Olivera BM]]
-[[Category: Mu-conotoxin]]
+[[Category: West PJ]]
-[[Category: Toxin]]
+[[Category: Yoshikami D]]

1q2j

From Proteopedia

Current revision

Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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