View source for 2ajw


==Structure of the cyclic conotoxin MII-6==
<StructureSection load='2ajw' size='340' side='right'caption='[[2ajw]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2ajw]] 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=2AJW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AJW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2ajw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ajw OCA], [https://pdbe.org/2ajw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ajw RCSB], [https://www.ebi.ac.uk/pdbsum/2ajw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ajw ProSAT]</span></td></tr>
</table>
== Function ==
[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> 
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== Publication Abstract from PubMed ==
Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the alpha-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.

Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII.,Clark RJ, Fischer H, Dempster L, Daly NL, Rosengren KJ, Nevin ST, Meunier FA, Adams DJ, Craik DJ Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13767-72. Epub 2005 Sep 14. PMID:16162671<ref>PMID:16162671</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2ajw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Conus magus]]
[[Category: Large Structures]]
[[Category: Adams DJ]]
[[Category: Clark RJ]]
[[Category: Craik DJ]]
[[Category: Daly NL]]
[[Category: Dempster L]]
[[Category: Fischer H]]
[[Category: Meunier FA]]
[[Category: Nevin ST]]
[[Category: Rosengren KJ]]