1m2c

From Proteopedia

(Difference between revisions)

Current revision

THREE-DIMENSIONAL STRUCTURE OF ALPHA-CONOTOXIN MII, NMR, 14 STRUCTURES

Structural highlights

1m2c is a 1 chain structure with sequence from Conus magus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 14 models
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CA12_CONMA Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them. This toxin blocks neuronal mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3-beta-2/CHRNA3-CHRNB2 > alpha-3-beta-4/CHRNA3-CHRNB4 = alpha-4-beta-2/CHRNA4-CHRNB2) (PubMed:15005608, PubMed:20145249). Also exhibits inhibition of D.melanogaster alpha-7/CHRNA7 nAChRs (PubMed:25466886). In addition, inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR with a higher potency on human (IC(50)=1.49 nM) than on rat receptors (IC(50)=31.5 nM) (PubMed:33523678). Its binding to alpha-3-beta-2/CHRNA3-CHRNB2 nAChR is prevented by alpha-conotoxin Lt1a, suggesting that the two toxins have overlapping binding sites (PubMed:20145249). In addition, both toxins have distinct nAChR binding mode (PubMed:20145249). In vivo, inhibits Ehrlich carcinoma growth and increase mouse survival (PubMed:32272633). These effects are greatly enhanced when the toxin is applied with the non-selective cyclooxygenase inhibitor indomethacin (PubMed:32272633).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Publication Abstract from PubMed

We have isolated a 16-amino acid peptide from the venom of the marine snail Conus magus which potently blocks nicotinic acetylcholine receptors (nAChRs) composed of alpha3beta2 subunits. This peptide, named alpha-conotoxin MII, was identified by electrophysiologically screening venom fractions against cloned nicotinic receptors expressed in Xenopus oocytes. The peptide's structure, which has been confirmed by mass spectrometry and total chemical synthesis, differs significantly from those of all previously isolated alpha-conotoxins. Disulfide bridging, however, is conserved. The toxin blocks the response to acetylcholine in oocytes expressing alpha3beta2 nAChRs with an IC50 of 0.5 nM and is 2-4 orders of magnitude less potent on other nAChR subunit combinations. We have recently reported the isolation and characterization of alpha-conotoxin ImI, which selectively targets homomeric alpha7 neuronal nAChRs. Yet other alpha-conotoxins selectively block the muscle subtype of nAChR. Thus, it is increasingly apparent that alpha-conotoxins represent a significant resource for ligands with which to probe structure-function relationships of various nAChR subtypes.

A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors.,Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM J Biol Chem. 1996 Mar 29;271(13):7522-8. PMID:8631783^[11]

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

References

↑ Kuryatov A, Olale F, Cooper J, Choi C, Lindstrom J. Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology. 2000 Oct;39(13):2570-90. PMID:11044728
↑ Everhart D, Cartier GE, Malhotra A, Gomes AV, McIntosh JM, Luetje CW. Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors. Biochemistry. 2004 Mar 16;43(10):2732-7. PMID:15005608 doi:10.1021/bi036180h
↑ McIntosh JM, Azam L, Staheli S, Dowell C, Lindstrom JM, Kuryatov A, Garrett JE, Marks MJ, Whiteaker P. Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol. 2004 Apr;65(4):944-52. PMID:15044624 doi:10.1124/mol.65.4.944
↑ Dutertre S, Nicke A, Lewis RJ. Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic acetylcholine receptor. J Biol Chem. 2005 Aug 26;280(34):30460-8. Epub 2005 Jun 1. PMID:15929983 doi:http://dx.doi.org/10.1074/jbc.M504229200
↑ Shiembob DL, Roberts RL, Luetje CW, McIntosh JM. Determinants of alpha-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit. Biochemistry. 2006 Sep 19;45(37):11200-7. PMID:16964981 doi:10.1021/bi0611715
↑ Luo S, Akondi KB, Zhangsun D, Wu Y, Zhu X, Hu Y, Christensen S, Dowell C, Daly NL, Craik DJ, Wang CI, Lewis RJ, Alewood PF, Michael McIntosh J. Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel microsite of the alpha3beta2 nicotinic receptor. J Biol Chem. 2010 Apr 16;285(16):12355-66. PMID:20145249 doi:10.1074/jbc.M109.079012
↑ Heghinian MD, Mejia M, Adams DJ, Godenschwege TA, Marí F. Inhibition of cholinergic pathways in Drosophila melanogaster by α-conotoxins. FASEB J. 2015 Mar;29(3):1011-8. PMID:25466886 doi:10.1096/fj.14-262733
↑ Osipov AV, Terpinskaya TI, Yanchanka T, Balashevich T, Zhmak MN, Tsetlin VI, Utkin YN. α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors. Mar Drugs. 2020 Apr 7;18(4):193. PMID:32272633 doi:10.3390/md18040193
↑ Hone AJ, Kaas Q, Kearns I, Hararah F, Gajewiak J, Christensen S, Craik DJ, McIntosh JM. Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs. J Med Chem. 2021 Feb 11;64(3):1685-1700. PMID:33523678 doi:10.1021/acs.jmedchem.0c01973
↑ Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM. A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem. 1996 Mar 29;271(13):7522-8. PMID:8631783
↑ Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM. A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem. 1996 Mar 29;271(13):7522-8. PMID:8631783

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/1m2c"

@@ Line 1: / Line 1: @@
 ==THREE-DIMENSIONAL STRUCTURE OF ALPHA-CONOTOXIN MII, NMR, 14 STRUCTURES==
-<StructureSection load='1m2c' size='340' side='right'caption='[[1m2c]], [[NMR_Ensembles_of_Models | 14 NMR models]]' scene=''>
+<StructureSection load='1m2c' size='340' side='right'caption='[[1m2c]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1m2c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conma Conma]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M2C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1m2c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_magus Conus magus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M2C FirstGlance]. <br>
-</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><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, 14 models</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=1m2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m2c OCA], [https://pdbe.org/1m2c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m2c RCSB], [https://www.ebi.ac.uk/pdbsum/1m2c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m2c ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/CA2_CONMA CA2_CONMA]] Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them. This toxin blocks neuronal mammalian nAChRs (alpha-6 or -3/beta-2 or -3 > alpha-3/beta-2 > alpha-3/beta-4 = alpha-4/beta-2).<ref>PMID:11044728</ref> <ref>PMID:8631783</ref>
+[https://www.uniprot.org/uniprot/CA12_CONMA CA12_CONMA] Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them. This toxin blocks neuronal mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3-beta-2/CHRNA3-CHRNB2 > alpha-3-beta-4/CHRNA3-CHRNB4 = alpha-4-beta-2/CHRNA4-CHRNB2) (PubMed:15005608, PubMed:20145249). Also exhibits inhibition of D.melanogaster alpha-7/CHRNA7 nAChRs (PubMed:25466886). In addition, inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR with a higher potency on human (IC(50)=1.49 nM) than on rat receptors (IC(50)=31.5 nM) (PubMed:33523678). Its binding to alpha-3-beta-2/CHRNA3-CHRNB2 nAChR is prevented by alpha-conotoxin Lt1a, suggesting that the two toxins have overlapping binding sites (PubMed:20145249). In addition, both toxins have distinct nAChR binding mode (PubMed:20145249). In vivo, inhibits Ehrlich carcinoma growth and increase mouse survival (PubMed:32272633). These effects are greatly enhanced when the toxin is applied with the non-selective cyclooxygenase inhibitor indomethacin (PubMed:32272633).<ref>PMID:11044728</ref> <ref>PMID:15005608</ref> <ref>PMID:15044624</ref> <ref>PMID:15929983</ref> <ref>PMID:16964981</ref> <ref>PMID:20145249</ref> <ref>PMID:25466886</ref> <ref>PMID:32272633</ref> <ref>PMID:33523678</ref> <ref>PMID:8631783</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Conma]]
+[[Category: Conus magus]]
 [[Category: Large Structures]]
-[[Category: Koerber, S C]]
+[[Category: Koerber SC]]
-[[Category: Mcintosh, J M]]
+[[Category: Mcintosh JM]]
-[[Category: Olivera, B M]]
+[[Category: Olivera BM]]
-[[Category: Rivier, J E]]
+[[Category: Rivier JE]]
-[[Category: Shon, K J]]
+[[Category: Shon KJ]]
-[[Category: Cholinergic modulation]]
-[[Category: Dopamine release]]
-[[Category: Neuronal nicotinic acetylcholine receptor inhibitor]]
-[[Category: Neurotoxin]]
-[[Category: Presynaptic nicotinic acetylcholine receptor blocker]]
-[[Category: Subtype specific ligand]]

1m2c

From Proteopedia

Current revision

THREE-DIMENSIONAL STRUCTURE OF ALPHA-CONOTOXIN MII, NMR, 14 STRUCTURES

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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