1lgl

From Proteopedia

(Difference between revisions)

Revision as of 13:36, 10 September 2015

Solution structure of HERG-specific scorpion toxin BeKm-1

Structural highlights

1lgl is a 1 chain structure with sequence from Buthus eupeus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[KGX21_MESEU] Blocks human and/or rat Kv11.1/KCNH2/ERG1, Kv11.2/KCNH6/ERG2 and Kv11.3/KCNH7/ERG3 by binding to channel outer vestibule (S5P domain) with a 1:1 stoichiometry. Inhibition data are the following: hERG1 (reversible, Kd=7.7 nM (PubMed:16497878), IC(50)=3.3 nM (PubMed:11136720), IC(50)=11.9 nM (PubMed:21205913)), rERG1 (reversible, Kd=19 nM) (PubMed:16497878), hERG2 (reversible, Kd=77 nM) (PubMed:16497878), rERG2 (irreversible, Kd=4.2 nM) (PubMed:16497878), hERG3 (reversible, Kd=11.5 nM) (PubMed:16497878) and rERG3 (reversible, Kd=747 nM) (PubMed:16497878) potassium channels. Has also a minimal effect on rat ELK1/KCNH4 potassium channels (9% inhibition at 100 nM (PubMed:15137031)). Both this toxin and CnErgTx1 (AC Q86QT3) share mechanism of action and have overlapping binding sites on ERG1 (PubMed:12719233). The potency of these two toxins is not affected by elevating potassium ion concentration from 2 to 98 mM (PubMed:12719233). In addition, at high toxin concentrations, block of ERG1 macroscopic currents by these two toxins is incomplete (88%) (PubMed:12719233). The blockade by this toxin is preferentially closed channel state-dependent, with a component of open, but not inactive state-dependent blockade (PubMed:12860380). This toxin produces a concentration-dependent prolongation of QTc in the isolated rabbit heart (16.3% at 100 nM) (PubMed:21205913).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The scorpion toxin BeKm-1 is unique among a variety of known short scorpion toxins affecting potassium channels in its selective action on ether-a-go-go-related gene (ERG)-type channels. BeKm-1 shares the common molecular scaffold with other short scorpion toxins. The toxin spatial structure resolved by NMR consists of a short alpha-helix and a triple-stranded antiparallel beta-sheet. By toxin mutagenesis study we identified the residues that are important for the binding of BeKm-1 to the human ERG K+ (HERG) channel. The most critical residues (Tyr-11, Lys-18, Arg-20, Lys-23) are located in the alpha-helix and following loop whereas the "traditional" functional site of other short scorpion toxins is formed by residues from the beta-sheet. Thus the unique location of the binding site of BeKm-1 provides its specificity toward the HERG channel.

New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1.,Korolkova YV, Bocharov EV, Angelo K, Maslennikov IV, Grinenko OV, Lipkin AV, Nosyreva ED, Pluzhnikov KA, Olesen SP, Arseniev AS, Grishin EV J Biol Chem. 2002 Nov 8;277(45):43104-9. Epub 2002 Jul 31. PMID:12151390^[7]

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

References

↑ Korolkova YV, Kozlov SA, Lipkin AV, Pluzhnikov KA, Hadley JK, Filippov AK, Brown DA, Angelo K, Strobaek D, Jespersen T, Olesen SP, Jensen BS, Grishin EV. An ERG channel inhibitor from the scorpion Buthus eupeus. J Biol Chem. 2001 Mar 30;276(13):9868-76. Epub 2001 Jan 2. PMID:11136720 doi:http://dx.doi.org/10.1074/jbc.M005973200
↑ Zhang M, Korolkova YV, Liu J, Jiang M, Grishin EV, Tseng GN. BeKm-1 is a HERG-specific toxin that shares the structure with ChTx but the mechanism of action with ErgTx1. Biophys J. 2003 May;84(5):3022-36. PMID:12719233 doi:http://dx.doi.org/10.1016/S0006-3495(03)70028-9
↑ Milnes JT, Dempsey CE, Ridley JM, Crociani O, Arcangeli A, Hancox JC, Witchel HJ. Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Lett. 2003 Jul 17;547(1-3):20-6. PMID:12860380
↑ 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
↑ Qu Y, Fang M, Gao B, Chui RW, Vargas HM. BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart. J Pharmacol Exp Ther. 2011 Apr;337(1):2-8. doi: 10.1124/jpet.110.176883. Epub, 2010 Dec 23. PMID:21205913 doi:http://dx.doi.org/10.1124/jpet.110.176883
↑ Filippov AK, Kozlov SA, Pluzhnikov KA, Grishin EV, Brown DA. M-type K+ current inhibition by a toxin fron the scorpion Buthus eupeus. FEBS Lett. 1996 Apr 22;384(3):277-80. PMID:8617371
↑ Korolkova YV, Bocharov EV, Angelo K, Maslennikov IV, Grinenko OV, Lipkin AV, Nosyreva ED, Pluzhnikov KA, Olesen SP, Arseniev AS, Grishin EV. New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1. J Biol Chem. 2002 Nov 8;277(45):43104-9. Epub 2002 Jul 31. PMID:12151390 doi:10.1074/jbc.M204083200

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1lgl"

@@ Line 2: / Line 2: @@
 <StructureSection load='1lgl' size='340' side='right' caption='[[1lgl]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1lgl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mesobuthus_eupeus Mesobuthus eupeus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LGL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1LGL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1lgl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buthus_eupeus Buthus eupeus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LGL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1LGL FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1lgl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lgl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1lgl RCSB], [http://www.ebi.ac.uk/pdbsum/1lgl PDBsum]</span></td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1lgl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lgl OCA], [http://pdbe.org/1lgl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1lgl RCSB], [http://www.ebi.ac.uk/pdbsum/1lgl PDBsum]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/KGX21_MESEU KGX21_MESEU]] Blocks human and/or rat Kv11.1/KCNH2/ERG1, Kv11.2/KCNH6/ERG2 and Kv11.3/KCNH7/ERG3 by binding to channel outer vestibule (S5P domain) with a 1:1 stoichiometry. Inhibition data are the following: hERG1 (reversible, Kd=7.7 nM (PubMed:16497878), IC(50)=3.3 nM (PubMed:11136720), IC(50)=11.9 nM (PubMed:21205913)), rERG1 (reversible, Kd=19 nM) (PubMed:16497878), hERG2 (reversible, Kd=77 nM) (PubMed:16497878), rERG2 (irreversible, Kd=4.2 nM) (PubMed:16497878), hERG3 (reversible, Kd=11.5 nM) (PubMed:16497878) and rERG3 (reversible, Kd=747 nM) (PubMed:16497878) potassium channels. Has also a minimal effect on rat ELK1/KCNH4 potassium channels (9% inhibition at 100 nM (PubMed:15137031)). Both this toxin and CnErgTx1 (AC Q86QT3) share mechanism of action and have overlapping binding sites on ERG1 (PubMed:12719233). The potency of these two toxins is not affected by elevating potassium ion concentration from 2 to 98 mM (PubMed:12719233). In addition, at high toxin concentrations, block of ERG1 macroscopic currents by these two toxins is incomplete (88%) (PubMed:12719233). The blockade by this toxin is preferentially closed channel state-dependent, with a component of open, but not inactive state-dependent blockade (PubMed:12860380). This toxin produces a concentration-dependent prolongation of QTc in the isolated rabbit heart (16.3% at 100 nM) (PubMed:21205913).<ref>PMID:11136720</ref> <ref>PMID:12719233</ref> <ref>PMID:12860380</ref> <ref>PMID:16497878</ref> <ref>PMID:21205913</ref> <ref>PMID:8617371</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 13: / Line 15: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1lgl" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 20: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Mesobuthus eupeus]]
+[[Category: Buthus eupeus]]
 [[Category: Angelo, K]]
 [[Category: Arseniev, A S]]

1lgl

From Proteopedia

Revision as of 13:36, 10 September 2015

Solution structure of HERG-specific scorpion toxin BeKm-1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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