2mfy
From Proteopedia
(Difference between revisions)
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| - | + | ==Non-reducible analogues of alpha-conotoxin Vc1.1: [2,8]-trans dicarba Vc1.1== | |
| - | + | <StructureSection load='2mfy' size='340' side='right' caption='[[2mfy]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[2mfy]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MFY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MFY FirstGlance]. <br> | |
| - | ==Function== | + | </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">[[2mfx|2mfx]], [[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=2mfy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mfy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2mfy RCSB], [http://www.ebi.ac.uk/pdbsum/2mfy PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
[[http://www.uniprot.org/uniprot/CA1A_CONVC 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.<ref>PMID:12779345</ref> <ref>PMID:15770155</ref> | [[http://www.uniprot.org/uniprot/CA1A_CONVC 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.<ref>PMID:12779345</ref> <ref>PMID:15770155</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:23768016</ref> | |
| - | + | ||
| - | == | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | + | </div> | |
| - | [[Category: Lierop, B J.Van | + | == References == |
| - | [[Category: Macraild, C A | + | <references/> |
| - | [[Category: Norton, R S | + | __TOC__ |
| - | [[Category: Robinson, A J | + | </StructureSection> |
| - | [[Category: Robinson, S D | + | [[Category: Lierop, B J.Van]] |
| + | [[Category: Macraild, C A]] | ||
| + | [[Category: Norton, R S]] | ||
| + | [[Category: Robinson, A J]] | ||
| + | [[Category: Robinson, S D]] | ||
[[Category: Dicarba]] | [[Category: Dicarba]] | ||
[[Category: Toxin]] | [[Category: Toxin]] | ||
Revision as of 21:38, 25 December 2014
Non-reducible analogues of alpha-conotoxin Vc1.1: [2,8]-trans dicarba Vc1.1
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