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蚂蚁淘在线 / 品牌中心 / Smartox / Smartox/Selective blocker of ERG1 channel/13BEK001-00100/0.1mg

Smartox/Selective blocker of ERG1 channel/13BEK001-00100/0.1mg

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￥1684.80

货号：13BEK001-00100

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BeKm-1toxin isapeptidetoxinthathasbeenisolatedfromthevenomoftheCentralAsianscorpion Buthuseupeus.BeKm-1toxin hasbeenreportedtobeahighlyselectiveinhibitorofthehuman ether-a-go-goERG1channel(hERG1). BeKm-1 inhibitshERG1channelsexpressedinHEK-293cellswithan IC₅₀ of3.3nM,buthasnoeffectat100nMonhumanEAG,humanSK1,ratSK2,humanIK,humanBK,KCNQ1/KCNE1,KCNQ2/KCNQ3,andKCNQ4channels.IthasalsominimaleffectsonratELK1channel. BeKm-1 inhibitsthehumanERG1+KCNE1combinationtransientlyexpressedinHEK-293cellswithanIC₅₀valueintherangeof10to30nM. BeKm-1toxin preferentiallyblockshumanERGchannelthroughtheclosed(resting)state,althoughsomeopenchannelblockadeisalsoreportedtooccur.

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Description:

Productcode:N/A.Categories:hERG/Kv11.1,Potassiumchannels.Tag:hERG.

AAsequence: Arg-Pro-Thr-Asp-Ile-Lys-Cys⁷-Ser-Glu-Ser-Tyr-Gln-Cys¹³-Phe-Pro-Val-Cys¹⁷-Lys-Ser-Arg-Phe-Gly-Lys-Thr-Asn-Gly-Arg-Cys²⁸-Val-Asn-Gly-Phe-Cys³³-Asp-Cys³⁵-Phe-OH
Disulfidebonds: Cys⁷-Cys²⁸,Cys¹³-Cys³³,andCys¹⁷-Cys³⁵
Length(aa): 36
Formula: C₁₇₄H₂₆₁N₅₁O₅₂S₆
MolecularWeight: 4091.70Da
Appearance:Whitelyophilizedsolid
Solubility: waterandsalinebuffer
CASnumber: Notavailable
Source: Synthetic
Purityrate: >97%

Reference:

InteractionsimulationofhERGK+channelwithitsspecificBeKm-1peptide:insightsintotheselectivityofmolecularrecognition.

PotassiumchannelsshowahugevariABIlityintheaffinitywhenrecognizingenormousbioactivepeptides,andtheelucidationoftheirrecognitionmechanismremainsagreatchallengeduetoanundeterminedpeptide-channelcomplexstructure.Here,weemployedcombinedcomputationmethodstostudythespecificbindingofBeKm-1peptidetothehERGpotassiumchannel,whichisanessentialdeterminantofthelong-QTsyndrome.Bytheuseofasegment-assemblyhomologymodelingmethod,theclosed-statehERGstructurecontainingunusuallongerS5Plinkerwassuccessfullyconstructed.Ithasa“petunia”shape,whilefour“petals”ofsymmetricallydistributedS5Psegmentsalwaysdecentralize.StartingfromthehERGandBeKm-1structures,aconsiderablyreasonableBeKm-1-hERGcomplexstructurewasthenscreenedoutandidentifiedbyprotein-proteindocking,moleculardynamics(MD)simulations,andcalculationofrelativebindingfreeenergies.Thevalidityofthispredictedcomplexwasfurtherassessedbycomputationalalanine-scanning,withtheresultscorrelatingreasonablywellwithexperimentaldata.Inthenovelcomplexstructure,fourconsiderablyflexIBLeS5PlinkersarefarfromtheBeKm-1peptide.TheBeKm-1mainlyusesitshelicalregiontoassociatethechanneloutervestibule,exceptfortheS5Plinkerregion;however,structuralanalysisfurtherimpliesthisneutralporeregionwithwigglingS5PlinkerishighlybeneficialtothebindingofBeKm-1withlowerpositivecharges.ThemostcriticalLys18ofBeKm-1plugsitssidechainintothechannelselectivityfilter,whilethesecondarilyimportantArg20formsthreehydrogenbondswithspatiallyneighboringresiduesinthehERGchannel.Differentfromtheclassicalpeptide-K+channelinteractionmainlyinducedbyelectrostaticinteraction,asynergeticeffectoftheelectrostaticandvanderWaalsinteractionswasfoundtomediatethemolecularrecognitionbetweenBeKm-1andthehERGchannel.AndthisspecificbindingprocessisrevealedtobeadynamicchangeofreductionofbindingfreeenergyandconformationalrearrangementmainlyintheinterfaceofbothBeKm-1andthehERGchannel.AllthesestructuralandenergyfeaturesyielddeepinsightsonthehighselectivebindingmechanismofhERG-specificpeptides,presentadiversityofpeptide-K+channelinteractions,andalsoprovideimportantcluestofurtherstudystructure-functionrelationshipsofthehERGchannel.

YiH.,etal.(2007)InteractionsimulationofhERGK+channelwithitsspecificBeKm-1peptide:insightsintotheselectivityofmolecularrecognition.JProteomeRes.PMID17269718

BeKm-1,apeptideinhibitorofhumanether-a-go-go-relatedgenepotassiumcurrents,prolongsQTcintervalsinisolatedrabbitheart.

Drug-inducedcardiacarrhythmia,specificallyTorsadesdepointes,isassociatedwithQT/QTcintervalprolongation,thusprolongationoftheQTintervalisconsideredasabioMarkerforTorsadesdepointesrisk(NEnglJMed350:1013-1022,2004).Specificinhibitionofhumanether-a-go-go-relatedgene(hERG)potassiumchannelshasbeenrecognizedasthemainmechanismforQTprolongation(CardiovascRes58:32-45,2003).Thismechanismhasbeendemonstratedforavarietyofsmall-moleculeagents,whichaccesstheinnerporeofthehERGchannelpreferentiallyfrominsidethecell.PeptideinhibitorsofhERG,suchasBeKm-1,interactwiththeextracellularaminoacidresiduesclosetotheexternalporeregionofthechannel.Inthisstudy,theisolatedrabbitheartwasusedtoassesswhetherBeKm-1couldinduceQTcprolongationlikedofetilideandN-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide(E-4031).Fiveheartswereperfusedwith10and100nMBeKm-1sequentially.ECGparametersandleftventricularcontractilityweremeasuredwithspontaneouslybeatinghearts.BothconcentrationsofBeKm-1prolongedQTcintervalssignificantlyandconcentration-dependently(4.7and16.3%at10and100nM,respectively).WhenevaluatedfortheirinhibitoryeffectinahERGfunctionalassay,BeKm-1,dofetilide,andE-4031causedQTcprolongationatconcentrationsthatcausedsignificanthERGchannelinhibition.Lastly,twopolyclonalanti-hERGantibodieswerealsoassessedinthehERGchannelassayandfoundtobedevoidofanyinhibitoryeffect.TheseresultsindicatedthattheisolatedrabbitheartassaycanbeusedtomeasureQTcchangescausedbyspecifichERGinhibitionbypeptidesthatspecificallyblocktheexternalporeregionofthechannel.

QuY.,etal.(2011)BeKm-1,apeptideinhibitorofhumanether-a-go-go-relatedgenepotassiumcurrents,prolongsQTcintervalsinisolatedrabbitheart.JPharmacolExpTher.PMID21205913

PreferentialclosedchannelblockadeofHERGpotassiumcurrentsbychemicallysynthesisedBeKm-1scorpiontoxin.

ThescorpiontoxinpeptideBeKm-1wassynthesisedbyfluorenylmethoxycarbonylsolidphasechemistryandfoldedbyairoxidation.Thepeptide’seffectsonheterologoushumanether-a-go-go-relatedgenepotassiumcurrent(I(HERG))inHEK293cellswereassessedusing‘whole-cell’patchclamp.BlockadeofI(HERG)byBeKm-1wasconcentration-dependent,temperature-dependent,andrapidinonsetandreversibility.Blockadealsoexhibitedinversevoltagedependence,inversedependenceondurationofdepolarisation,andreverseuse-andfrequency-dependence.BlockadebyBeKm-1andrecombinantergtoxin,anotherscorpiontoxinknowntoblockHERG,differedintheirrecoveryfromHERGcurrentinactivationelicitedbystrongdepolarisationandintheirabilitytoblockHERGwhenthechannelswerealreadyactivated.WeconcludethatsyntheticBeKm-1toxinblocksHERGpreferentiallythroughaclosed(resting)statechannelblockademechanism,althoughsomeopenchannelblockadealsooccurs.

MilnesJ.,etal.(2003)PreferentialclosedchannelblockadeofHERGpotassiumcurrentsbychemicallysynthesisedBeKm-1scorpiontoxin.FEBSLetters.PMID12860380

NewbindingsiteoncommonmolecularscaffoldprovidesHERGchannelspecificityofscorpiontoxinBeKm-1.

ThescorpiontoxinBeKm-1isuniqueamongavarietyofknownshortscorpiontoxinsaffectingpotassiumchannelsinitsselectiveactiononether-a-go-go-relatedgene(ERG)-typechannels.BeKm-1sharesthecommonmolecularscaffoldwithothershortscorpiontoxins.ThetoxinspatialstructureresolvedbyNMRconsistsofashortalpha-helixandatriple-strandedantiparallelbeta-sheet.BytoxinmutagenesisstudyweidentifiedtheresiduesthatareimportantforthebindingofBeKm-1tothehumanERGK+(HERG)channel.Themostcriticalresidues(Tyr-11,Lys-18,Arg-20,Lys-23)arelocatedinthealpha-helixandfollowingloopwhereasthe“trADItional”functionalsiteofothershortscorpiontoxinsisformedbyresiduesfromthebeta-sheet.ThustheuniquelocationofthebindingsiteofBeKm-1providesitsspecificitytowardtheHERGchannel.

KorolkovaY.,etal.(2002)NewBindingSiteonCommonMolecularScaffoldProvidesHERGChannelSpecificityofScorpionToxinBeKm-1.JBC.PMID:12151390

AnERGchannelinhibitorfromthescorpionButhuseupeus.

TheisolationofthepeptideinhibitorofM-typeK(+)current,BeKm-1,fromthevenomoftheCentralAsianscorpionButhuseupeushasbeendescribedpreviously(FillipovA.K.,Kozlov,S.A.,Pluzhnikov,K.A.,Grishin,E.V.,andBrown,D.A.(1996)FEBSLett.384,277-280).Herewereportthecloning,expression,andselectivityofBeKm-1.Afull-lengthCDNAof365nucleotidesencodingtheprecursorofBeKm-1wasisolatedusingtherapidamplificationofcDNAendspolymerasechainreactiontechniquefrommRNAobtainedfromscorpiontelsons.SequenceanalysisofthecDNArevealedthattheprecursorcontainsasignalpeptideof21aminoacidresidues.Thematuretoxinconsistsof36aminoacidresidues.BeKm-1belongstothefamilyofscorpionvenompotassiumchannelblockersandrepresentsanewsubgroupofthesetoxins.TherecombinantBeKm-1wasproducedasaProteinAfusionproductintheperiplasmofEscherichiacoli.Aftercleavageandhighperformanceliquidchromatographypurification,recombinantBeKm-1displayedthesamepropertiesasthenativetoxin.ThreeBeKm-1mutants(R27K,F32K,andR27K/F32K)weregenerated,purified,andcharacterized.Recombinantwild-typeBeKm-1andthethreemutantspartlyinhibitedthenativeM-likecurrentinNG108-15at100nm.TheeffectoftherecombinantBeKm-1ondifferentK(+)channelswasalsostudied.BeKm-1inhibitedhERG1channelswithanIC(50)of3.3nm,buthadnoeffectat100nmonhEAG,hSK1,rSK2,hIK,hBK,KCNQ1/KCNE1,KCNQ2/KCNQ3,KCNQ4channels,andminimaleffectonrELK1.Thus,BeKm-1wasshowntobeanovelspecificblockerofhERG1potassiumchannels.

KorolkovaY.,etal.(2001)AnERGChannelInhibitorfromtheScorpionButhuseupeus.JBC.PMID:11136720

Smartox生物素ProTx-I电压门控钠通道和T型Cav的阻断剂毒素I（ProTx-1；β-theraphotoxin-Tp1a）是一种毒素，最初是从Prixopelma pruriens（秘鲁绿色天鹅绒狼蛛）的毒液中分离出来的。此毒素可逆地抑制抗河豚毒素（TTX）的通道 Na v 1.8（IC 50 = 27 nM）和 Na v 1.2，Na v 1.5和Na v 1.7 ，IC 50 值为50至100 nM。此外， ProTx-I 改变了T型Ca v 3.1通道的电压依赖性活动（IC 50 = 50 nM），而不会影响灭活的电压依赖性。生物素ProTx-I是ProTx-I的生物素标签版本。

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