2j15
From Proteopedia
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| - | [[Image:2j15.jpg|left|200px]] | ||
| - | < | + | ==Cyclic MrIA: An exceptionally stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter.== |
| - | + | <StructureSection load='2j15' size='340' side='right'caption='[[2j15]]' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[2j15]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_marmoreus Conus marmoreus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J15 FirstGlance]. <br> | |
| - | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 21 models</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></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=2j15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j15 OCA], [https://pdbe.org/2j15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j15 RCSB], [https://www.ebi.ac.uk/pdbsum/2j15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j15 ProSAT]</span></td></tr> | |
| - | + | </table> | |
| - | + | == Function == | |
| - | + | [https://www.uniprot.org/uniprot/CTA1A_CONMR CTA1A_CONMR] Chi-conotoxins inhibit the neuronal noradrenaline transporter (NET/SLC6A2) (PubMed:11528421, PubMed:12837768, PubMed:12885787, PubMed:16154696). Activity has been described on both human (inhibition of norepinephrine uptake is IC(50)=1.26 uM) and rat (pIC(50)=6.21 corresponding IC(50)=0.16 uM) transporters (PubMed:11528421, PubMed:12885787). Acts as a reversible non-competitive inhibitor (PubMed:11528421).<ref>PMID:11528421</ref> <ref>PMID:12837768</ref> <ref>PMID:12885787</ref> <ref>PMID:16154696</ref> | |
| - | + | <div style="background-color:#fffaf0;"> | |
| - | == | + | == Publication Abstract from PubMed == |
Conotoxins, disulfide-rich peptides from the venom of cone snails, have created much excitement over recent years due to their potency and specificity for ion channels and their therapeutic potential. One recently identified conotoxin, MrIA, a 13-residue member of the chi-conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. In the current study, we show that the beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET. Furthermore, the cyclic version has increased resistance to trypsin digestion relative to the native peptide, an intriguing result because the cleavage site for the trypsin is not close to the cyclization site. The use of peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular disulfide-rich peptides. | Conotoxins, disulfide-rich peptides from the venom of cone snails, have created much excitement over recent years due to their potency and specificity for ion channels and their therapeutic potential. One recently identified conotoxin, MrIA, a 13-residue member of the chi-conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. In the current study, we show that the beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET. Furthermore, the cyclic version has increased resistance to trypsin digestion relative to the native peptide, an intriguing result because the cleavage site for the trypsin is not close to the cyclization site. The use of peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular disulfide-rich peptides. | ||
| - | + | Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter.,Lovelace ES, Armishaw CJ, Colgrave ML, Wahlstrom ME, Alewood PF, Daly NL, Craik DJ J Med Chem. 2006 Nov 2;49(22):6561-8. PMID:17064074<ref>PMID:17064074</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: | + | <div class="pdbe-citations 2j15" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: | + | [[Category: Conus marmoreus]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Alewood PF]] |
| - | + | [[Category: Armishaw CJ]] | |
| + | [[Category: Colgrave ML]] | ||
| + | [[Category: Craik DJ]] | ||
| + | [[Category: Daly NL]] | ||
| + | [[Category: Lovelace ES]] | ||
| + | [[Category: Walstrom ME]] | ||
Current revision
Cyclic MrIA: An exceptionally stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter.
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