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| | ==NMR solution structure of omega-conotoxin [K10]GVIA, a cyclic cysteine knot peptide== | | ==NMR solution structure of omega-conotoxin [K10]GVIA, a cyclic cysteine knot peptide== |
| - | <StructureSection load='1tr6' size='340' side='right'caption='[[1tr6]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='1tr6' size='340' side='right'caption='[[1tr6]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| | <table><tr><td colspan='2'>[[1tr6]] 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=1TR6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TR6 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[1tr6]] 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=1TR6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TR6 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>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1omc|1omc]], [[2cco|2cco]]</div></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>, <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=1tr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tr6 OCA], [https://pdbe.org/1tr6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tr6 RCSB], [https://www.ebi.ac.uk/pdbsum/1tr6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tr6 ProSAT]</span></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=1tr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tr6 OCA], [https://pdbe.org/1tr6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tr6 RCSB], [https://www.ebi.ac.uk/pdbsum/1tr6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tr6 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CO16A_CONGE CO16A_CONGE]] Omega-conotoxins act at presynaptic membranes, they bind and block voltage-gated calcium channels (Cav).
| + | [https://www.uniprot.org/uniprot/O16A_CONGE O16A_CONGE] Omega-conotoxins act at presynaptic membranes, they bind and block voltage-gated calcium channels (Cav). This toxin blocks N-type calcium channels (Cav2.2/CACNA1B) with a high potency (it displaces [125I]GVIA with an IC(50)=3.7-38 pM) (PubMed:10938268, PubMed:11724570).<ref>PMID:10938268</ref> <ref>PMID:11724570</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | [[Category: Conus geographus]] | | [[Category: Conus geographus]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Adams, D J]] | + | [[Category: Adams DJ]] |
| - | [[Category: Beedle, A M]] | + | [[Category: Beedle AM]] |
| - | [[Category: Doering, C J]] | + | [[Category: Doering CJ]] |
| - | [[Category: Lewis, R J]] | + | [[Category: Lewis RJ]] |
| - | [[Category: Mould, J]] | + | [[Category: Mould J]] |
| - | [[Category: Schroeder, C I]] | + | [[Category: Schroeder CI]] |
| - | [[Category: Yasuda, T]] | + | [[Category: Yasuda T]] |
| - | [[Category: Zamponi, G W]] | + | [[Category: Zamponi GW]] |
| - | [[Category: Cysteine knot]]
| + | |
| - | [[Category: Four-loop frame work]]
| + | |
| - | [[Category: Toxin]]
| + | |
| Structural highlights
Function
O16A_CONGE Omega-conotoxins act at presynaptic membranes, they bind and block voltage-gated calcium channels (Cav). This toxin blocks N-type calcium channels (Cav2.2/CACNA1B) with a high potency (it displaces [125I]GVIA with an IC(50)=3.7-38 pM) (PubMed:10938268, PubMed:11724570).[1] [2]
Publication Abstract from PubMed
The omega-conotoxins from fish-hunting cone snails are potent inhibitors of voltage-gated calcium channels. The omega-conotoxins MVIIA and CVID are selective N-type calcium channel inhibitors with potential in the treatment of chronic pain. The beta and alpha(2)delta-1 auxiliary subunits influence the expression and characteristics of the alpha(1B) subunit of N-type channels and are differentially regulated in disease states, including pain. In this study, we examined the influence of these auxiliary subunits on the ability of the omega-conotoxins GVIA, MVIIA, CVID and analogues to inhibit peripheral and central forms of the rat N-type channels. Although the beta3 subunit had little influence on the on- and off-rates of omega-conotoxins, coexpression of alpha(2)delta with alpha(1B) significantly reduced on-rates and equilibrium inhibition at both the central and peripheral isoforms of the N-type channels. The alpha(2)delta also enhanced the selectivity of MVIIA, but not CVID, for the central isoform. Similar but less pronounced trends were also observed for N-type channels expressed in human embryonic kidney cells. The influence of alpha(2)delta was not affected by oocyte deglycosylation. The extent of recovery from the omega-conotoxin block was least for GVIA, intermediate for MVIIA, and almost complete for CVID. Application of a hyperpolarizing holding potential (-120 mV) did not significantly enhance the extent of CVID recovery. Interestingly, [R10K]MVIIA and [O10K]GVIA had greater recovery from the block, whereas [K10R]CVID had reduced recovery from the block, indicating that position 10 had an important influence on the extent of omega-conotoxin reversibility. Recovery from CVID block was reduced in the presence of alpha(2)delta in human embryonic kidney cells and in oocytes expressing alpha(1B-b). These results may have implications for the antinociceptive properties of omega-conotoxins, given that the alpha(2)delta subunit is up-regulated in certain pain states.
The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels.,Mould J, Yasuda T, Schroeder CI, Beedle AM, Doering CJ, Zamponi GW, Adams DJ, Lewis RJ J Biol Chem. 2004 Aug 13;279(33):34705-14. Epub 2004 May 27. PMID:15166237[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lewis RJ, Nielsen KJ, Craik DJ, Loughnan ML, Adams DA, Sharpe IA, Luchian T, Adams DJ, Bond T, Thomas L, Jones A, Matheson JL, Drinkwater R, Andrews PR, Alewood PF. Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J Biol Chem. 2000 Nov 10;275(45):35335-44. PMID:10938268 doi:10.1074/jbc.M002252200
- ↑ Favreau P, Gilles N, Lamthanh H, Bournaud R, Shimahara T, Bouet F, Laboute P, Letourneux Y, Ménez A, Molgó J, Le Gall F. A new omega-conotoxin that targets N-type voltage-sensitive calcium channels with unusual specificity. Biochemistry. 2001 Dec 4;40(48):14567-75. PMID:11724570 doi:10.1021/bi002871r
- ↑ Mould J, Yasuda T, Schroeder CI, Beedle AM, Doering CJ, Zamponi GW, Adams DJ, Lewis RJ. The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels. J Biol Chem. 2004 Aug 13;279(33):34705-14. Epub 2004 May 27. PMID:15166237 doi:10.1074/jbc.M310848200
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