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2mfx

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Revision as of 10:48, 11 September 2015

Non-reducible analogues of alpha-conotoxin Vc1.1: [2,8]-cis dicarba Vc1.1

Structural highlights

2mfx is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	,
Related:	2mfy, 2mg6
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[CA1A_CONVC] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This synthetic peptide (produced without hydroxyproline, nor 4-carboxyglutamate) is a neuronal nAChR antagonist that acts as a powerful analgesic. It blocks nAChRs composed of alpha-3 or -5/beta-2 (IC(50)=7.2 uM), alpha-3/beta-2 (IC(50)=7.3 uM), alpha-3/beta-4 (IC(50)=4.2 uM), alpha-3 or -5/beta-4 (IC(50)<30 uM), alpha-4/beta-2 (IC(50)<30 uM), alpha-4/beta-4 (IC(50)<30 uM) and alpha/beta/gamma/delta (IC(50)<30 uM) subunits.^[1] ^[2]

Publication Abstract from PubMed

Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus Conus, have evolved exquisite selectivity for receptors and ion channels of excitable tissue. One such peptide, alpha-conotoxin Vc1.1, is a 16-mer possessing an interlocked disulfide framework. Despite its emergence as a potent analgesic lead, the molecular target and mechanism of action of Vc1.1 have not been elucidated to date. In this paper we describe the regioselective synthesis of dicarba analogues of Vc1.1 using olefin metathesis. The ability of these peptides to inhibit acetylcholine-evoked current at rat alpha9alpha10 and alpha3beta4 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes has been assessed in addition to their ability to inhibit high voltage-activated (HVA) calcium channel current in isolated rat DRG neurons. Their solution structures were determined by NMR spectroscopy. Significantly, we have found that regioselective replacement of the native cystine framework with a dicarba bridge can be used to selectively tune the cyclic peptide's innate biological activity for one receptor over another. The 2,8-dicarba Vc1.1 isomer retains activity at gamma-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the alpha9alpha10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide's potent analgesic activity.

Dicarba alpha-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors.,van Lierop BJ, Robinson SD, Kompella SN, Belgi A, McArthur JR, Hung A, MacRaild CA, Adams DJ, Norton RS, Robinson AJ ACS Chem Biol. 2013 Aug 16;8(8):1815-21. doi: 10.1021/cb4002393. Epub 2013 Jun, 17. PMID:23768016^[3]

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

References

↑ Sandall DW, Satkunanathan N, Keays DA, Polidano MA, Liping X, Pham V, Down JG, Khalil Z, Livett BG, Gayler KR. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry. 2003 Jun 10;42(22):6904-11. PMID:12779345 doi:http://dx.doi.org/10.1021/bi034043e
↑ Lang PM, Burgstahler R, Haberberger RV, Sippel W, Grafe P. A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves. Neuroreport. 2005 Apr 4;16(5):479-83. PMID:15770155
↑ van Lierop BJ, Robinson SD, Kompella SN, Belgi A, McArthur JR, Hung A, MacRaild CA, Adams DJ, Norton RS, Robinson AJ. Dicarba alpha-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors. ACS Chem Biol. 2013 Aug 16;8(8):1815-21. doi: 10.1021/cb4002393. Epub 2013 Jun, 17. PMID:23768016 doi:http://dx.doi.org/10.1021/cb4002393

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/2mfx"

@@ Line 5: / Line 5: @@
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2mfy|2mfy]], [[2mg6|2mg6]]</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=2mfx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mfx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2mfx RCSB], [http://www.ebi.ac.uk/pdbsum/2mfx 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=2mfx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mfx OCA], [http://pdbe.org/2mfx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mfx RCSB], [http://www.ebi.ac.uk/pdbsum/2mfx PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2mfx" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

2mfx

From Proteopedia

Revision as of 10:48, 11 September 2015

Non-reducible analogues of alpha-conotoxin Vc1.1: [2,8]-cis dicarba Vc1.1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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