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2n8e

From Proteopedia

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Current revision

Three-dimensional structure of cyclic PVIIA

Structural highlights

2n8e is a 1 chain structure with sequence from Conus purpurascens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

O17A_CONPU Kappa-conotoxins bind and inhibit voltage-gated potassium channels (Kv). This toxin inhibits the drosophila Shaker channel (IC(50)=57-80 nM) (PubMed:12074021, PubMed:10818087, PubMed:27093300). In vivo, when tested in fish, this toxin induces hyperactivity, followed by continuous contraction and extension of major fins, without immobilization or death (PubMed:9417043, PubMed:12074021). Injection of this peptide together with the delta-conotoxin PVIA causes the sudden tetanus of prey (STOP) syndrome, which is a single, lethal 'fin-pop' in envenomed fish (PubMed:9417043, PubMed:12074021). When tested in mice, induces hyperactivity (PubMed:9417043).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Disulfide-rich peptides isolated from cone snails are of great interest as drug leads due to their high specificity and potency toward therapeutically relevant ion channels and receptors. They commonly contain the inhibitor cystine knot (ICK) motif comprising three disulfide bonds forming a knotted core. Here we report the successful enzymatic backbone cyclization of an ICK-containing peptide kappa-PVIIA, a 27-amino acid conopeptide from Conus purpurascens, using a mutated version of the bacterial transpeptidase, sortase A. Although a slight loss of activity was observed compared to native kappa-PVIIA, cyclic kappa-PVIIA is a functional peptide that inhibits the Shaker voltage-gated potassium (Kv) channel. Molecular modeling suggests that the decrease in potency may be related to the loss of crucial, but previously unidentified electrostatic interactions between the N-terminus of the peptide and the Shaker channel. This hypothesis was confirmed by testing an N-terminally acetylated kappa-PVIIA, which shows a similar decrease in activity. We also investigated the conformational dynamics and hydrogen bond network of cyc-PVIIA, both of which are important factors to be considered for successful cyclization of peptides. We found that cyc-PVIIA has the same conformational dynamics, but different hydrogen bond network compared to those of kappa-PVIIA. The ability to efficiently cyclize ICK peptides using sortase A will enable future protein engineering for this class of peptides and may help in the development of novel therapeutic molecules. Biotechnol. Bioeng. 2016;113: 2202-2212. (c) 2016 Wiley Periodicals, Inc.

Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide.,Kwon S, Bosmans F, Kaas Q, Cheneval O, Conibear AC, Rosengren KJ, Wang CK, Schroeder CI, Craik DJ Biotechnol Bioeng. 2016 Oct;113(10):2202-12. doi: 10.1002/bit.25993. Epub 2016, Aug 9. PMID:27093300^[7]

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

References

↑ Terlau H, Boccaccio A, Olivera BM, Conti F. The block of Shaker K+ channels by kappa-conotoxin PVIIA is state dependent. J Gen Physiol. 1999 Jul;114(1):125-40. PMID:10398696
↑ Jacobsen RB, Koch ED, Lange-Malecki B, Stocker M, Verhey J, Van Wagoner RM, Vyazovkina A, Olivera BM, Terlau H. Single amino acid substitutions in kappa-conotoxin PVIIA disrupt interaction with the shaker K+ channel. J Biol Chem. 2000 Aug 11;275(32):24639-44. doi: 10.1074/jbc.C900990199. PMID:10818087 doi:http://dx.doi.org/10.1074/jbc.C900990199
↑ Naranjo D. Inhibition of single Shaker K channels by kappa-conotoxin-PVIIA. Biophys J. 2002 Jun;82(6):3003-11. PMID:12023223 doi:http://dx.doi.org/S0006-3495(02)75641-5
↑ Terlau H, Shon KJ, Grilley M, Stocker M, Stuhmer W, Olivera BM. Strategy for rapid immobilization of prey by a fish-hunting marine snail. Nature. 1996 May 9;381(6578):148-51. PMID:12074021 doi:http://dx.doi.org/10.1038/381148a0
↑ Kwon S, Bosmans F, Kaas Q, Cheneval O, Conibear AC, Rosengren KJ, Wang CK, Schroeder CI, Craik DJ. Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide. Biotechnol Bioeng. 2016 Oct;113(10):2202-12. doi: 10.1002/bit.25993. Epub 2016, Aug 9. PMID:27093300 doi:http://dx.doi.org/10.1002/bit.25993
↑ Shon KJ, Stocker M, Terlau H, Stuhmer W, Jacobsen R, Walker C, Grilley M, Watkins M, Hillyard DR, Gray WR, Olivera BM. kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel. J Biol Chem. 1998 Jan 2;273(1):33-8. PMID:9417043
↑ Kwon S, Bosmans F, Kaas Q, Cheneval O, Conibear AC, Rosengren KJ, Wang CK, Schroeder CI, Craik DJ. Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide. Biotechnol Bioeng. 2016 Oct;113(10):2202-12. doi: 10.1002/bit.25993. Epub 2016, Aug 9. PMID:27093300 doi:http://dx.doi.org/10.1002/bit.25993

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/2n8e"

Categories: Conus purpurascens | Large Structures | Craik D | Kwon S | Schroeder C

@@ Line 1: / Line 1: @@
 ==Three-dimensional structure of cyclic PVIIA==
-<StructureSection load='2n8e' size='340' side='right'caption='[[2n8e]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2n8e' size='340' side='right'caption='[[2n8e]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2n8e]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N8E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2n8e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_purpurascens Conus purpurascens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N8E FirstGlance]. <br>
-</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene></td></tr>
+</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=2n8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n8e OCA], [https://pdbe.org/2n8e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n8e RCSB], [https://www.ebi.ac.uk/pdbsum/2n8e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n8e ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/CO17A_CONPU CO17A_CONPU]] Kappa-conotoxins bind and inhibit voltage-gated potassium channels (Kv). This toxin inhibits the Shaker channel from insects. The interaction site between the Shaker channel and this toxin is within the S5-S6 loop of the Shaker channel. In fish, this toxin induces hyperactivity, followed by continuous contraction and extension of major fins, without immobilization or death. Injection of this peptide together with the delta-conotoxin PVIA causes the sudden tetanus of prey (STOP) syndrome, which is a single, lethal "fin-pop" in envenomed fish. In mice, induces hyperactivity.<ref>PMID:10398696</ref> <ref>PMID:12023223</ref> <ref>PMID:12074021</ref> <ref>PMID:9417043</ref>
+[https://www.uniprot.org/uniprot/O17A_CONPU O17A_CONPU] Kappa-conotoxins bind and inhibit voltage-gated potassium channels (Kv). This toxin inhibits the drosophila Shaker channel (IC(50)=57-80 nM) (PubMed:12074021, PubMed:10818087, PubMed:27093300). In vivo, when tested in fish, this toxin induces hyperactivity, followed by continuous contraction and extension of major fins, without immobilization or death (PubMed:9417043, PubMed:12074021). Injection of this peptide together with the delta-conotoxin PVIA causes the sudden tetanus of prey (STOP) syndrome, which is a single, lethal 'fin-pop' in envenomed fish (PubMed:9417043, PubMed:12074021). When tested in mice, induces hyperactivity (PubMed:9417043).<ref>PMID:10398696</ref> <ref>PMID:10818087</ref> <ref>PMID:12023223</ref> <ref>PMID:12074021</ref> <ref>PMID:27093300</ref> <ref>PMID:9417043</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Conus purpurascens]]
 [[Category: Large Structures]]
-[[Category: Craik, D]]
+[[Category: Craik D]]
-[[Category: Kwon, S]]
+[[Category: Kwon S]]
-[[Category: Schroeder, C]]
+[[Category: Schroeder C]]
-[[Category: Cystine knot]]
-[[Category: Inhibitor]]
-[[Category: Toxin]]

2n8e

From Proteopedia

Current revision

Three-dimensional structure of cyclic PVIIA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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