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| - | [[Image:1s6x.gif|left|200px]]<br /><applet load="1s6x" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1s6x" /> | |
| - | '''Solution structure of VSTx'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Solution structure of VSTx== |
| - | VSTx1 is a voltage sensor toxin from the spider Grammostola spatulata that, inhibits KvAP, an archeabacterial voltage-activated K(+) channel whose, X-ray structure has been reported. Although the receptor for VSTx1 and the, mechanism of inhibition are unknown, the sequence of the toxin is related, to hanatoxin (HaTx) and SGTx, two toxins that inhibit eukaryotic, voltage-activated K(+) channels by binding to voltage sensors. VSTx1 has, been recently shown to interact equally well with lipid membranes that, contain zwitterionic or acidic phospholipids, and it has been proposed, that the toxin receptor is located within a region of the channel that is, submerged in the membrane. As a first step toward understanding the, inhibitory mechanism of VSTx1, we determined the three-dimensional, solution structure of the toxin using NMR. Although the structure of VSTx1, is similar to HaTx and SGTx in terms of molecular fold and amphipathic, character, the detailed positions of hydrophobic and surrounding charged, residues in VSTx1 are very different than what is seen in the other, toxins. The amphipathic character of VSTx1, notably the close apposition, of basic and hydrophobic residues on one face of the toxin, raises the, possibility that the toxin interacts with interfacial regions of the, membrane. We reinvestigated the partitioning of VSTx1 into lipid membranes, and find that VSTx1 partitioning requires negatively charged, phospholipids. Intrinsic tryptophan fluorescence and acrylamide quenching, experiments suggest that tryptophan residues on the hydrophobic surface of, VSTx1 have a diminished exposure to water when the toxin interacts with, membranes. The present results suggest that if membrane partitioning is, involved in the mechanism by which VSTx1 inhibits voltage-activated K(+), channels, then binding of the toxin to the channel would likely occur at, the interface between the polar headgroups and the hydrophobic phase of, the membrane. | + | <StructureSection load='1s6x' size='340' side='right'caption='[[1s6x]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1s6x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Grammostola_rosea Grammostola rosea]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S6X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1S6X FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 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=1s6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s6x OCA], [https://pdbe.org/1s6x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1s6x RCSB], [https://www.ebi.ac.uk/pdbsum/1s6x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1s6x ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/VSTX1_GRARO VSTX1_GRARO] Inhibits sodium channels Nav1.7/SCN9A and potassium channels Kv11.1/KCNH2. Also binds the voltage-sensor domain of the potassium channel KvAP (from the archaeon Aeropyrum pernix) with very slow apparent binding kinetics and affects channel gating. Reaches its target by dynamically partitioning into anionic or zwitterionic headgroup lipid membranes. May bind to the open state of KvAP.<ref>PMID:15241419</ref> <ref>PMID:15287735</ref> <ref>PMID:17002285</ref> <ref>PMID:19955179</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | VSTx1 is a voltage sensor toxin from the spider Grammostola spatulata that inhibits KvAP, an archeabacterial voltage-activated K(+) channel whose X-ray structure has been reported. Although the receptor for VSTx1 and the mechanism of inhibition are unknown, the sequence of the toxin is related to hanatoxin (HaTx) and SGTx, two toxins that inhibit eukaryotic voltage-activated K(+) channels by binding to voltage sensors. VSTx1 has been recently shown to interact equally well with lipid membranes that contain zwitterionic or acidic phospholipids, and it has been proposed that the toxin receptor is located within a region of the channel that is submerged in the membrane. As a first step toward understanding the inhibitory mechanism of VSTx1, we determined the three-dimensional solution structure of the toxin using NMR. Although the structure of VSTx1 is similar to HaTx and SGTx in terms of molecular fold and amphipathic character, the detailed positions of hydrophobic and surrounding charged residues in VSTx1 are very different than what is seen in the other toxins. The amphipathic character of VSTx1, notably the close apposition of basic and hydrophobic residues on one face of the toxin, raises the possibility that the toxin interacts with interfacial regions of the membrane. We reinvestigated the partitioning of VSTx1 into lipid membranes and find that VSTx1 partitioning requires negatively charged phospholipids. Intrinsic tryptophan fluorescence and acrylamide quenching experiments suggest that tryptophan residues on the hydrophobic surface of VSTx1 have a diminished exposure to water when the toxin interacts with membranes. The present results suggest that if membrane partitioning is involved in the mechanism by which VSTx1 inhibits voltage-activated K(+) channels, then binding of the toxin to the channel would likely occur at the interface between the polar headgroups and the hydrophobic phase of the membrane. |
| | | | |
| - | ==About this Structure==
| + | Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel.,Jung HJ, Lee JY, Kim SH, Eu YJ, Shin SY, Milescu M, Swartz KJ, Kim JI Biochemistry. 2005 Apr 26;44(16):6015-23. PMID:15835890<ref>PMID:15835890</ref> |
| - | 1S6X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1S6X OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel., Jung HJ, Lee JY, Kim SH, Eu YJ, Shin SY, Milescu M, Swartz KJ, Kim JI, Biochemistry. 2005 Apr 26;44(16):6015-23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15835890 15835890]
| + | </div> |
| - | [[Category: Protein complex]] | + | <div class="pdbe-citations 1s6x" style="background-color:#fffaf0;"></div> |
| - | [[Category: Eu, Y.J.]] | + | == References == |
| - | [[Category: Jung, H.J.]] | + | <references/> |
| - | [[Category: Kim, J.I.]] | + | __TOC__ |
| - | [[Category: double stranded antiparallel beta-sheet]] | + | </StructureSection> |
| - | [[Category: inhibitory cystine knot]]
| + | [[Category: Grammostola rosea]] |
| - | | + | [[Category: Large Structures]] |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 02:09:36 2007''
| + | [[Category: Eu YJ]] |
| | + | [[Category: Jung HJ]] |
| | + | [[Category: Kim JI]] |
| Structural highlights
Function
VSTX1_GRARO Inhibits sodium channels Nav1.7/SCN9A and potassium channels Kv11.1/KCNH2. Also binds the voltage-sensor domain of the potassium channel KvAP (from the archaeon Aeropyrum pernix) with very slow apparent binding kinetics and affects channel gating. Reaches its target by dynamically partitioning into anionic or zwitterionic headgroup lipid membranes. May bind to the open state of KvAP.[1] [2] [3] [4]
Publication Abstract from PubMed
VSTx1 is a voltage sensor toxin from the spider Grammostola spatulata that inhibits KvAP, an archeabacterial voltage-activated K(+) channel whose X-ray structure has been reported. Although the receptor for VSTx1 and the mechanism of inhibition are unknown, the sequence of the toxin is related to hanatoxin (HaTx) and SGTx, two toxins that inhibit eukaryotic voltage-activated K(+) channels by binding to voltage sensors. VSTx1 has been recently shown to interact equally well with lipid membranes that contain zwitterionic or acidic phospholipids, and it has been proposed that the toxin receptor is located within a region of the channel that is submerged in the membrane. As a first step toward understanding the inhibitory mechanism of VSTx1, we determined the three-dimensional solution structure of the toxin using NMR. Although the structure of VSTx1 is similar to HaTx and SGTx in terms of molecular fold and amphipathic character, the detailed positions of hydrophobic and surrounding charged residues in VSTx1 are very different than what is seen in the other toxins. The amphipathic character of VSTx1, notably the close apposition of basic and hydrophobic residues on one face of the toxin, raises the possibility that the toxin interacts with interfacial regions of the membrane. We reinvestigated the partitioning of VSTx1 into lipid membranes and find that VSTx1 partitioning requires negatively charged phospholipids. Intrinsic tryptophan fluorescence and acrylamide quenching experiments suggest that tryptophan residues on the hydrophobic surface of VSTx1 have a diminished exposure to water when the toxin interacts with membranes. The present results suggest that if membrane partitioning is involved in the mechanism by which VSTx1 inhibits voltage-activated K(+) channels, then binding of the toxin to the channel would likely occur at the interface between the polar headgroups and the hydrophobic phase of the membrane.
Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel.,Jung HJ, Lee JY, Kim SH, Eu YJ, Shin SY, Milescu M, Swartz KJ, Kim JI Biochemistry. 2005 Apr 26;44(16):6015-23. PMID:15835890[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lee SY, MacKinnon R. A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom. Nature. 2004 Jul 8;430(6996):232-5. PMID:15241419 doi:http://dx.doi.org/10.1038/nature02632
- ↑ Ruta V, MacKinnon R. Localization of the voltage-sensor toxin receptor on KvAP. Biochemistry. 2004 Aug 10;43(31):10071-9. PMID:15287735 doi:http://dx.doi.org/10.1021/bi049463y
- ↑ Bemporad D, Sands ZA, Wee CL, Grottesi A, Sansom MS. Vstx1, a modifier of Kv channel gating, localizes to the interfacial region of lipid bilayers. Biochemistry. 2006 Oct 3;45(39):11844-55. PMID:17002285 doi:http://dx.doi.org/10.1021/bi061111z
- ↑ Redaelli E, Cassulini RR, Silva DF, Clement H, Schiavon E, Zamudio FZ, Odell G, Arcangeli A, Clare JJ, Alagon A, de la Vega RC, Possani LD, Wanke E. Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels. J Biol Chem. 2010 Feb 5;285(6):4130-42. doi: 10.1074/jbc.M109.054718. Epub 2009, Dec 2. PMID:19955179 doi:http://dx.doi.org/10.1074/jbc.M109.054718
- ↑ Jung HJ, Lee JY, Kim SH, Eu YJ, Shin SY, Milescu M, Swartz KJ, Kim JI. Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel. Biochemistry. 2005 Apr 26;44(16):6015-23. PMID:15835890 doi:http://dx.doi.org/10.1021/bi0477034
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