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| - | {{Seed}} | |
| - | [[Image:1q2j.png|left|200px]] | |
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| - | <!-- | + | ==Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA== |
| - | The line below this paragraph, containing "STRUCTURE_1q2j", creates the "Structure Box" on the page. | + | <StructureSection load='1q2j' size='340' side='right'caption='[[1q2j]]' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <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> |
| - | or leave the SCENE parameter empty for the default display.
| + | </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=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> |
| - | {{STRUCTURE_1q2j| PDB=1q2j | SCENE= }}
| + | <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 == |
| | + | 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===
| + | 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<ref>PMID:12970353</ref> |
| | | | |
| - | | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | <!--
| + | </div> |
| - | The line below this paragraph, {{ABSTRACT_PUBMED_12970353}}, adds the Publication Abstract to the page
| + | <div class="pdbe-citations 1q2j" style="background-color:#fffaf0;"></div> |
| - | (as it appears on PubMed at http://www.pubmed.gov), where 12970353 is the PubMed ID number.
| + | == References == |
| - | --> | + | <references/> |
| - | {{ABSTRACT_PUBMED_12970353}}
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==About this Structure== | + | [[Category: Conus stercusmuscarum]] |
| - | Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q2J OCA].
| + | [[Category: Large Structures]] |
| - | | + | [[Category: Bulaj G]] |
| - | ==Reference==
| + | [[Category: Keizer DW]] |
| - | 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:[http://www.ncbi.nlm.nih.gov/pubmed/12970353 12970353]
| + | [[Category: Lee EF]] |
| - | [[Category: Bulaj, G.]] | + | [[Category: Norton RS]] |
| - | [[Category: Keizer, D W.]] | + | [[Category: Olivera BM]] |
| - | [[Category: Lee, E F.]] | + | [[Category: West PJ]] |
| - | [[Category: Norton, R S.]] | + | [[Category: Yoshikami D]] |
| - | [[Category: Olivera, B M.]] | + | |
| - | [[Category: West, P J.]] | + | |
| - | [[Category: Yoshikami, D.]] | + | |
| - | [[Category: Mu-conotoxin]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 08:28:32 2008''
| + | |
| Structural highlights
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
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