Smartox/ERG1通道选择性阻滞剂/13BEK001-00100/0.1mg
商品编号：
13BEK001-00100
品牌：
smartox-biotech
市场价：
¥1684.80
美元价：
1296.00
产品分类：
酸碱缓冲液
联系Q Q：
3392242852
电话号码：
4000-520-616
电子邮箱：
info@ebiomall.com
商品介绍
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-293cellswithanIC50 valueintherangeof10to30nM. BeKm-1toxin preferentiallyblockshumanERGchannelthroughtheclosed(resting)state,althoughsomeopenchannelblockadeisalsoreportedtooccur.
Recentlyquoted
Description:
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
品牌介绍
Smartox Biotechnology 是全球唯一一家专门生产动物毒液多肽毒素，用于细胞离子通道功能研究的生物医药公司。多肽毒素在生物制药领域具有重要的使用价值。Smartox Biotechnology 于 2009 年由来自 Grenoble 神经科学研究所 (Grenoble Institute of Neuroscience) 的 Michel de waard 博士创立, Smartox Biotechnology 专门研究动物毒液，制作合成多种毒液中的多肽成分（常称为毒素）。 De Waard 博士研究离子通道与毒素多肽的关系，尤其是鉴定、开发毒素多肽作为治疗性分子或细胞穿透肽 (cell penetrating peptides, CPP) 。其研究团队在毒液分离，药理性活性肽鉴定、富半胱氨酸肽定性、制作和优化等方面具有独特、丰富的经验。 2010 年， Smartox Biotechnolgy 被法国研究部 (Ministry of Research) 授予“新兴企业 OSEO 奖 (OSEO prize for emerging businesses) ”。
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