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| - | [[Image:1wqk.gif|left|200px]]<br /><applet load="1wqk" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1wqk" /> | |
| - | '''Solution structure of APETx1, a specific peptide inhibitor of human Ether-a-go-go-related gene potassium channels from the venom of the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin'''<br /> | |
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| - | ==Overview== | + | ==Solution structure of APETx1, a specific peptide inhibitor of human Ether-a-go-go-related gene potassium channels from the venom of the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin== |
| - | APETx1 is a 42-amino acid toxin purified from the venom of the sea anemone, Anthopleura elegantissima. This cysteine-rich peptide possesses three, disulfide bridges (C4-C37, C6-C30, and C20-C38). Its pharmacological, target is the Ether-a-gogo potassium channel. We herein determine the, solution structure of APETx1 by use of conventional two-dimensional 1H-NMR, techniques followed by torsion angle dynamics and refinement protocols., The calculated structure of APETx1 belongs to the disulfide-rich all-beta, structural family, in which a three-stranded anti-parallel beta-sheet is, the only secondary structure. APETx1 is the first Ether-a-gogo effector, discovered to fold in this way. We therefore compare the structure of, APETx1 to those of the two other known effectors of the Ether-a-gogo, potassium channel, CnErg1 and BeKm-1, and analyze the topological, disposition of key functional residues proposed by analysis of the, electrostatic anisotropy. The interacting surface is made of a patch of, aromatic residues (Y5, Y32, and F33) together with two basic residues (K8, and K18) at the periphery of the surface. We pinpoint the absence of the, central lysine present in the functional surface of the two other, Ether-a-gogo effectors. | + | <StructureSection load='1wqk' size='340' side='right'caption='[[1wqk]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1wqk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Anthopleura_elegantissima Anthopleura elegantissima]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1WQK FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 25 models</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=1wqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wqk OCA], [https://pdbe.org/1wqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1wqk RCSB], [https://www.ebi.ac.uk/pdbsum/1wqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1wqk ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BDS1_ANTEL BDS1_ANTEL] Peptide with both antimicrobial and neurotoxin activities. This toxin acts both on ERG potassium channels and sodium channels (PubMed:12815161,PubMed:16497878, PubMed:17473056, PubMed:22972919). It potently and reversibly inhibits human Kv11.1/KCNH2/ERG1 (IC(50)=34 nM) (PubMed:12815161, PubMed:16497878, PubMed:17473056), rat Kv11.1/KCNH2/ERG1 (PubMed:16497878) and Kv11.3/KCNH7/ERG3 (PubMed:17473056) voltage-gated potassium channels in a similar potency. It acts as a gating-modifier toxin that shifts the voltage-dependence of ERG activation in the positive direction and suppresses its current amplitudes elicited by strong depolarizing pulses (PubMed:12815161, PubMed:17473056). On sodium channels, it blocks Nav1.2/SCN2A (EC(50)=31 nM), Nav1.3/SCN3A, Nav1.4/SCN4A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.8/SCN10A (EC(50)=92 nM) (PubMed:22972919). It may act by binding at site 1 or close by, only when the pore is in an open configuration (PubMed:22972919). Shows antibacterial activity against the Gram-negative bacterium S.typhimurium, but not on the bacteria B.subtilis, S.aureus, and P.aeruginosa (PubMed:28796463). In vivo, this toxin does not induce neurotoxic symptoms when injected into mice (PubMed:12815161).<ref>PMID:12815161</ref> <ref>PMID:16497878</ref> <ref>PMID:17473056</ref> <ref>PMID:22972919</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | APETx1 is a 42-amino acid toxin purified from the venom of the sea anemone Anthopleura elegantissima. This cysteine-rich peptide possesses three disulfide bridges (C4-C37, C6-C30, and C20-C38). Its pharmacological target is the Ether-a-gogo potassium channel. We herein determine the solution structure of APETx1 by use of conventional two-dimensional 1H-NMR techniques followed by torsion angle dynamics and refinement protocols. The calculated structure of APETx1 belongs to the disulfide-rich all-beta structural family, in which a three-stranded anti-parallel beta-sheet is the only secondary structure. APETx1 is the first Ether-a-gogo effector discovered to fold in this way. We therefore compare the structure of APETx1 to those of the two other known effectors of the Ether-a-gogo potassium channel, CnErg1 and BeKm-1, and analyze the topological disposition of key functional residues proposed by analysis of the electrostatic anisotropy. The interacting surface is made of a patch of aromatic residues (Y5, Y32, and F33) together with two basic residues (K8 and K18) at the periphery of the surface. We pinpoint the absence of the central lysine present in the functional surface of the two other Ether-a-gogo effectors. |
| | | | |
| - | ==About this Structure==
| + | Solution structure of APETx1 from the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin.,Chagot B, Diochot S, Pimentel C, Lazdunski M, Darbon H Proteins. 2005 May 1;59(2):380-6. PMID:15726634<ref>PMID:15726634</ref> |
| - | 1WQK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Anthopleura_elegantissima Anthopleura elegantissima]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1WQK OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Solution structure of APETx1 from the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin., Chagot B, Diochot S, Pimentel C, Lazdunski M, Darbon H, Proteins. 2005 May 1;59(2):380-6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15726634 15726634]
| + | </div> |
| | + | <div class="pdbe-citations 1wqk" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Anthopleura elegantissima]] | | [[Category: Anthopleura elegantissima]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Chagot, B.]] | + | [[Category: Chagot B]] |
| - | [[Category: Darbon, H.]] | + | [[Category: Darbon H]] |
| - | [[Category: Diochot, S.]] | + | [[Category: Diochot S]] |
| - | [[Category: Lazdunski, M.]] | + | [[Category: Lazdunski M]] |
| - | [[Category: Pimentel, C.]] | + | [[Category: Pimentel C]] |
| - | [[Category: anthopleura elegantissima]]
| + | |
| - | [[Category: apetx1]]
| + | |
| - | [[Category: herg]]
| + | |
| - | [[Category: nmr]]
| + | |
| - | [[Category: potassium channel inhibitor]]
| + | |
| - | [[Category: sea anemone toxin]]
| + | |
| - | [[Category: structure determination]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 05:36:41 2007''
| + | |
| Structural highlights
Function
BDS1_ANTEL Peptide with both antimicrobial and neurotoxin activities. This toxin acts both on ERG potassium channels and sodium channels (PubMed:12815161,PubMed:16497878, PubMed:17473056, PubMed:22972919). It potently and reversibly inhibits human Kv11.1/KCNH2/ERG1 (IC(50)=34 nM) (PubMed:12815161, PubMed:16497878, PubMed:17473056), rat Kv11.1/KCNH2/ERG1 (PubMed:16497878) and Kv11.3/KCNH7/ERG3 (PubMed:17473056) voltage-gated potassium channels in a similar potency. It acts as a gating-modifier toxin that shifts the voltage-dependence of ERG activation in the positive direction and suppresses its current amplitudes elicited by strong depolarizing pulses (PubMed:12815161, PubMed:17473056). On sodium channels, it blocks Nav1.2/SCN2A (EC(50)=31 nM), Nav1.3/SCN3A, Nav1.4/SCN4A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.8/SCN10A (EC(50)=92 nM) (PubMed:22972919). It may act by binding at site 1 or close by, only when the pore is in an open configuration (PubMed:22972919). Shows antibacterial activity against the Gram-negative bacterium S.typhimurium, but not on the bacteria B.subtilis, S.aureus, and P.aeruginosa (PubMed:28796463). In vivo, this toxin does not induce neurotoxic symptoms when injected into mice (PubMed:12815161).[1] [2] [3] [4]
Publication Abstract from PubMed
APETx1 is a 42-amino acid toxin purified from the venom of the sea anemone Anthopleura elegantissima. This cysteine-rich peptide possesses three disulfide bridges (C4-C37, C6-C30, and C20-C38). Its pharmacological target is the Ether-a-gogo potassium channel. We herein determine the solution structure of APETx1 by use of conventional two-dimensional 1H-NMR techniques followed by torsion angle dynamics and refinement protocols. The calculated structure of APETx1 belongs to the disulfide-rich all-beta structural family, in which a three-stranded anti-parallel beta-sheet is the only secondary structure. APETx1 is the first Ether-a-gogo effector discovered to fold in this way. We therefore compare the structure of APETx1 to those of the two other known effectors of the Ether-a-gogo potassium channel, CnErg1 and BeKm-1, and analyze the topological disposition of key functional residues proposed by analysis of the electrostatic anisotropy. The interacting surface is made of a patch of aromatic residues (Y5, Y32, and F33) together with two basic residues (K8 and K18) at the periphery of the surface. We pinpoint the absence of the central lysine present in the functional surface of the two other Ether-a-gogo effectors.
Solution structure of APETx1 from the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin.,Chagot B, Diochot S, Pimentel C, Lazdunski M, Darbon H Proteins. 2005 May 1;59(2):380-6. PMID:15726634[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Diochot S, Loret E, Bruhn T, Beress L, Lazdunski M. APETx1, a new toxin from the sea anemone Anthopleura elegantissima, blocks voltage-gated human ether-a-go-go-related gene potassium channels. Mol Pharmacol. 2003 Jul;64(1):59-69. PMID:12815161 doi:http://dx.doi.org/10.1124/mol.64.1.59
- ↑ Restano-Cassulini R, Korolkova YV, Diochot S, Gurrola G, Guasti L, Possani LD, Lazdunski M, Grishin EV, Arcangeli A, Wanke E. Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system. Mol Pharmacol. 2006 May;69(5):1673-83. Epub 2006 Feb 23. PMID:16497878 doi:http://dx.doi.org/10.1124/mol.105.019729
- ↑ Zhang M, Liu XS, Diochot S, Lazdunski M, Tseng GN. APETx1 from sea anemone Anthopleura elegantissima is a gating modifier peptide toxin of the human ether-a-go-go- related potassium channel. Mol Pharmacol. 2007 Aug;72(2):259-68. doi: 10.1124/mol.107.035840. Epub 2007 May , 1. PMID:17473056 doi:http://dx.doi.org/10.1124/mol.107.035840
- ↑ Peigneur S, Beress L, Moller C, Mari F, Forssmann WG, Tytgat J. A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J. 2012 Dec;26(12):5141-51. doi: 10.1096/fj.12-218479. Epub 2012 Sep 12. PMID:22972919 doi:http://dx.doi.org/10.1096/fj.12-218479
- ↑ Chagot B, Diochot S, Pimentel C, Lazdunski M, Darbon H. Solution structure of APETx1 from the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin. Proteins. 2005 May 1;59(2):380-6. PMID:15726634 doi:10.1002/prot.20425
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