µ-conotoxinGIIIBisa22aminoacidconopeptideoriginallyisolatedfromthevenomofthepiscivorousmarinesnailConusgeographus.µ-conotoxinGIIIBadoptsacompactstructureconsistingofadistorted310-helixandasmallß-hairpin.µ-conotoxinGIIIBisstABIlizedbythreedisulphidebridgesandishighlyenrichedinlysineandarginineresidues,formingpotentialsitesofinteractionwithNachannels.Anunusualfeatureisthepresenceofthreehydroxyprolineresidues.µ-conotoxinGIIIBisausefulprobetodiscriminatebetweenneuronalandmusclesodiumchannelsasitexhibitsatleasta1000-foldspecificityformuscleversusnervesodiumchannels.µ-ConotoxinGIIIBselectivelyblocksNav1.4voltage-dependentsodiumchannels,whicharepredominantlyexpressedinmuscle,withanaffinitycloseto20nM.µ-ConotoxinGIIIBappearstophysicallyoccludethechannelporebybindingonsiteIoftheNa+channel.
Description:
AAsequence:Arg-Asp-Cys3-Cys4-Thr-Hyp-Hyp-Arg-Lys-Cys10-Lys-Asp-Arg-Arg-Cys15-Lys-Hyp-Met-Lys-Cys20-Cys21-Ala-NH2
Disulfidebonds:Cys3-Cys15,Cys4-Cys20andCys10-Cys21
Length(aa):22
Formula:C101H175N39O30S7
MolecularWeight:2640.26Da
Appearance:Whitelyophilizedsolid
Solubility:waterandsalinebuffer
CASnumber:
Source:Synthetic
Purityrate:>97%
Reference:
MolecularBasisofIsoform-specificμ-ConotoxinBlockofCardiac,SkeletalMuscle,andBrainNa+Channels
mu-Conotoxins(mu-CTXs)blockskeletalmuscleNa(+)channelswithanaffinity1-2ordersofmagnitudehigherthancardiacandbrainNa(+)channels.Althoughanumberofconservedporeresiduesarerecognizedascriticaldeterminantsofmu-CTXblock,themolecularbasisofisoform-specifictoxinsensitivityremainsunresolved.SequencecomparisonofthedomainII(DII)S5-S6loopsofratskeletalmuscle(mu1,Na(v)1.4),humanheart(hh1,Na(v)1.5),andratbrain(rb1,Na(v)1.1)Na(+)channelsrevealssubstantialdivergenceintheirN-terminalS5-PlinkerseventhoughtheP-S6andC-terminalPsegmentsarealmostidentical.WeusedNa(v)1.4asthebackboneandsystematicallyconvertedtheseDIIS5-PisoformvariantstothecorrespondingresiduesinNa(v)1.1andNa(v)1.5.TheNa(v)1.4–>Na(v)1.5variantsubstitutionsV724R,C725S,A728S,D730S,andC731S(Na(v)1.4numbering)reducedblockofNa(v)1.4by4-,86-,12-,185-,and55-foldrespectively,renderingtheskeletalmuscleisoformmore“cardiac-like.”Conversely,anNa(v)1.5–>Na(v)1.4chimericconstructinwhichtheNa(v)1.4DIIS5-PlinkerreplacestheanalogoussegmentinNa(v)1.5showedenhancedmu-CTXblock.However,thesevariantdeterminantsareconservedbetweenNa(v)1.1andNa(v)1.4andthuscannotexplaintheirdifferentsensitivitiestomu-CTX.ComparisonoftheirsequencesrevealstwovariantsatNa(v)1.4positions729and732:SerandAsninNa(v)1.4comparedwithThrandLysinNa(v)1.1,respectively.ThedoublemutationS729T/N732KrenderedNa(v)1.4more“brain-like”(30-folddownwardarrowinblock),andtheconversemutationT925S/K928NinNa(v)1.1reproducedthehighaffinityblockingphenotypeofNa(v)1.4.WeconcludethattheDIIS5-Plinker,althoughlyingoutsidetheconventionalion-conductingpore,playsaprominentroleinmu-CTXbinding,thusshapingisoform-specifictoxinsensitivity.
RonaldA.Li, etal.(2003)MolecularBasisofIsoform-specificμ-ConotoxinBlockofCardiac,SkeletalMuscle,andBrainNa+ Channels. JBC. PMID: 12471026
Conusgeographustoxinsthatdiscriminatebetweenneuronalandmusclesodiumchannels
Wedescribethepropertiesofafamilyof22-aminoacidpeptides,themu-conotoxins,whichareusefulprobesforinvestigatingvoltage-dependentsodiumchannelsofexcitabletissues.Themu-conotoxinsarepresentinthevenomofthepiscivorousmarinesnail,ConusgeographusL.Wehavepurifiedsevenhomologsofthemu-conotoxinsetanddeterminedtheiraminoacidsequences,asfollows,whereHyp=trans-4-hydroxyproline.GIIIAR.D.C.C.T.Hyp.Hyp.K.K.C.K.D.R.Q.C.K.Hyp.Q.R.C.C.A-NH2[Pro6]GIIIAR.D.C.C.T.P.Hyp.K.K.C.K.D.R.Q.C.K.Hyp.Q.R.C.C.A-NH2[Pro7]GIIIAR.D.C.C.T.Hyp.P.K.K.C.K.D.R.Q.C.R.Hyp.Q.R.C.C.A-NH2GIIIBR.D.C.C.T.Hyp.Hyp.R.K.C.K.D.R.R.C.K.Hyp.M.K.C.C.A-NH2[Pro6]GIIIBR.D.C.C.T.P.Hyp.R.K.C.K.D.R.R.C.K.Hyp.M.K.C.C.A-NH2[Pro7]GIIIBR.D.C.C.T.Hyp.P.R.K.C.K.D.R.R.C.K.Hyp.M.K.C.C.A-NH2GIIICR.D.C.C.T.Hyp.Hyp.K.K.C.K.D.R.R.C.K.Hyp.L.K.C.C.A-NH2.Usingthemajorpeptide(GIIIA)inelectrophysiologicalstudiesonnerve-musclepreparationsandinsinglechannelstudiesusingplanarlipidbilayers,wehaveestablishedthatthetoxinblocksmusclesodiumchannels,whilehavingnodiscernIBLeeffectonnerveorbrainsodiumchannels.InbilayerstheblockingkineticsofGIIIAwerederivedbystatisticalanalysisofdiscretetransitionsbetweenblockedandunblockedstatesofbatrachotoxin-activatedsodiumchannelsfromratmuscle.Thekineticsconformtoasingle-site,reversiblebindingequilibriumwithavoltage-dependentbindingconstant.ThemeasuredvalueoftheequilibriumKDforGIIIAis100nMatOmV,decreasinge-fold/34mVofhyperpolarization.Thisvoltagedependenceofblockingissimilartothatoftetrodotoxinandsaxitoxinasmeasuredbythesametechnique.Thetissuespecificityandkineticcharacteristicssuggestthatthemu-conotoxinsmayserveasusefulligandstodistinguishsodiumchannelsubtypesindifferenttissues.
CruzLJ, etal. (1985)Conusgeographustoxinsthatdiscriminatebetweenneuronalandmusclesodiumchannels. JBC. PMID: 2410412
NovelStructuralDeterminantsofm-Conotoxin(GIIIB)BlockinRatSkeletalMuscle(m1)Na+Channels
mu-Conotoxin(mu-CTX)specificallyoccludestheporeofvoltage-dependentNa(+)channels.IntheratskeletalmuscleNa(+)channel(mu1),weexaminedthecontributionofchargedresiduesbetweenthePloopsandS6inallfourdomainstomu-CTXblock.ConversionofthenegativelychargeddomainII(DII)residuesAsp-762andGlu-765tocysteineincreasedtheIC(50)formu-CTXblockbyapproximately100-fold(wild-type=22.3+/-7.0nm;D762C=2558+/-250nm;E765C=2020+/-379nm).Restorationorreversalofchargebyexternalmodificationofthecysteine-substitutedchannelswithmethanethiosulfonatereagents(methanethiosulfonateethylsulfonate(MTSES)andmethanethiosulfonateethylammonium(MTSEA))didnotaffectmu-CTXblock(D762C:IC(50,MTSEA+)=2165.1+/-250nm;IC(50,MTSES-)=2753.5+/-456.9nm;E765C:IC(50,MTSEA+)=2200.1+/-550.3nm;IC(50,MTSES-)=3248.1+/-2011.9nm)comparedwiththeirunmodifiedcounterparts.Incontrast,thecharge-conservingmutationsD762E(IC(50)=21.9+/-4.3nm)andE765D(IC(50)=22.0+/-7.0nm)preservedwild-typeblockingbehavior,whereasthechargereversalmutantsD762K(IC(50)=4139.9+/-687.9nm)andE765K(IC(50)=4202.7+/-1088.0nm)destabilizedmu-CTXblockevenfurther,suggestingaprominentelectrostaticcomponentoftheinteractionsbetweentheseDIIresiduesandmu-CTX.Kineticanalysisofmu-CTXblockrevealsthatthechangesintoxinsensitivityarelargelyduetoacceleratedtoxindissociation(k(off))rateswithlittlechangesinassociation(k(on))rates.Weconcludethattheacidicresiduesatpositions762and765arekeydeterminantsofmu-CTXblock,primarilybyvirtueoftheirnegativecharge.TheinabilityofthebulkyMTSESorMTSEAsidechaintomodifymu-CTXsensitivityplacesstericconstraintsonthesitesoftoxininteraction.
RonaldA.Li, etal. (2000)NovelStructuralDeterminantsofm-Conotoxin(GIIIB)BlockinRatSkeletalMuscle(m1)Na+ Channels.JBC.PMID: 10859326
HyperpolarizedshiftsinthevoltagedependenceoffastinactivationofNav1.4andNav1.5inaratmodelofcriticalillnessmyopathy
Criticalillnessmyopathyisadisorderinwhichskeletalmusclebecomeselectricallyinexcitable.Wepreviouslydemonstratedthatashiftinthevoltagedependenceoffastinactivationofsodiumcurrentscontributestoinexcitabilityofaffectedfibresinananimalmodelofcriticalillnessmyopathyinwhichdenervatedratskeletalmuscleistreatedwithcorticosteroids(steroid-denervated;SD).InthecurrentstudyweexaminedwhetherexpressionofNav1.5contributestothealteredvoltagedependenceofsodiumchannelinactivationinSDmuscle.WeusedTTXandmu-conotoxinGIIIBtoselectivelyblockNav1.4inSDmuscleandfoundthatthelevelofNav1.5didnotcorrelatecloselywiththeshiftinfastinactivation.Surprisingly,wefoundthatthevoltagedependenceofinactivationofNav1.4wassimilartothatofNav1.5inskeletalmuscleinvivo.Inseverelyaffectedfibres,inactivationofbothNav1.4andNav1.5wasshiftedtowardshyperpolarizedpotentials.Weexaminedtheroleofdenervationandsteroidtreatmentintheshiftofthevoltagedependenceofinactivationandfoundthatbothdenervationandsteroidtreatmentcontributetotheshiftininactivation.OurresultssuggestthatmodulationofthevoltagedependenceofinactivationofbothNav1.4andNav1.5invivocontributestolossofelectricalexcitabilityinSDmuscle.
GregoryN.FilatovandMarkM.Rich(2004)HyperpolarizedshiftsinthevoltagedependenceoffastinactivationofNav1.4andNav1.5inaratmodelofcriticalillnessmyopathy. J.Physiol. PMID: 15254148
Smartox Biotechnolgy的多肽毒素产品如下：
1. 作用于钠离子通道(Sodium channel)的毒素
Toxin name | Catalog # | Target |
Phrixotoxin-3 | 13PHX003 | Selective blocker of Nav1.2 |
µ-conotoxin GIIIB | CON020 | Selective blocker of Nav1.4 |
µ-conotoxin CnIIIC | CON021 | Selective blocker of Nav1.4 |
μ-conotoxin PIIIA | 08CON006 | Selective blocker of Nav1.4 |
Jingzhaotoxin-III | 12JZH003 | Selective blocker of Nav1.5 |
ProTx-II | 07PTX002 | Selective blocker of Nav1.7 |
ProTx-II Biotin | 12PTB002 | Selective blocker of Nav1.7 |
ProTx-I | 12PTX001 | Blocker of Nav1.8, Nav1.2, Nav1.5, Nav1.7 |
Huwentoxin-I | 07HWT001 | Blocker of TTX-S |
Huwentoxin-IV | 08HWT002 | Blocker of TTX-S |
Hainantoxin-III | 13HTX003 | Blocker of TTX-S |
Hainantoxin-IV | 12HTX001 | Blocker of TTX-S |
GsAF-I | 12GSF001 | Blocker of TTX-S |
GsAF-II | 12GSF002 | Blocker of TTX-S |
2. 作用于钾离子通道(Potassium channel)的毒素
Toxin name | Catalog # | Target |
KCa channels | ||
Apamin 蜜蜂神经毒素 | 08APA001 | SK1, SK2, SK3 |
Charybdotoxin 蝎毒素 | 11CHA001 | KCa1.1, KCa3.1 - Kv1.2, Kv1.3, Kv1.6 |
Iberiotoxin | 12IBX001 | KCa1.1 |
Leiurotoxin 1 (Scyllatoxin) | 10LEI001 | SK1, SK2, SK3 |
Tamapin | 10TAM001 | SK1, SK2, SK3 |
Kaliotoxin-1 | 08KTX002 | BK, Kv1.1, Kv1.2, Kv1.3 |
Kv channels | ||
ShK | 08SHK001 | Kv1.3, Kv1.1, Kv1.4, Kv1.6 |
TMR-ShK | SAT001 | Kv1.3, Kv1.1 |
Margatoxin | 08MAG001 | Kv1.3 |
(Dap22)-ShK | 13SHD001 | Kv1.3 |
ADWX-1 | 13ADW001 | Kv1.3 |
HsTx1 | 08NEU001 | Kv1.3, Kv1.2 |
Agitoxin-2 | 13AGI002 | Kv1.3, Kv1.1 |
Maurotoxin | 08MAR001 | Kv1.2, KCa3.1 |
Guangxitoxin 1E | 11GUA002 | Kv2.1, Kv2.2 |
Stromatoxin 1 NEW | SCT01 | Kv2.1, Kv2.2 |
Kaliotoxin-1 | 08KTX002 | BK, Kv1.1, Kv1.2, Kv1.3 |
Charybdotoxin | 11CHA001 | KCa1.1, KCa3.1 - Kv1.2, Kv1.3, Kv1.6 |
Phrixotoxin-2 | PHX002 | Kv4.2, Kv4.3 |
AmmTx3 NEW | AMX001 | A-type potassium channels |
Inwardly rectifying potassium channels | ||
TertiapinQ | 08TER001 | Kir1.1, Kir3.1/3.4, Kir3.1/3.2-KCa1.1 |
hERG/Kv11.1 | ||
BeKm-1 | 13BEK001 | ERG1 |
3. 作用于钙离子通道(Calcium channel)的毒素
Toxin name | Catalog # | Target |
High voltage-gated Ca2+ channels | ||
ω-agatoxin IVA | 11AGA001 | P/Qtype |
ω-Conotoxin MVIIC | 08CON002 | P/Qtype, N-type |
ω-Conotoxin MVIIA | 08CON001 | N-type |
ω-Conotoxin GVIA | 08CON003 | N-type |
ω-Conotoxin SO3 | 08CON013 | N-type |
Huwentoxin I | 07HWT001 | N-type |
ProTx-II | 07PTX002 | T-type, L-type |
Intermediate voltage-gated Ca2+ channels | ||
SNX482 | 08SNX002 | R-type |
Low voltage-gated Ca2+ channels | ||
ProTx-I | 12PTX001 | T-type |
ProTx-II | 07PTX002 | T-type, L-type |
Ryanodine receptors | ||
Maurocalcine | 07PAU001 | Ryr1 |
4. 作用于氯离子通道(Chloride channel)的毒素
Toxin name | Catalog # | Target |
Chlorotoxin | 08CHL001 | Blocker of small conductance Cl- channels |
GaTx1 | 13GTX001 | Selective blocker of CFTR channel |
GaTx2 | 10GTX002 | Selective blocker of ClC-2 channel |
5. 作用于乙酰胆碱受体(Acetylcholine receptor)的毒素
Toxin name | Catalog # | Target |
α-conotoxin PeIA | 13CON017 | α9α10, α3β2 subunits |
α-Conotoxin PrXA | 13CON016 | α1/β1/ε/δ, α1/β1/γ/δ subunits |
Waglerin-1 | 12WAG001 | MusclenAChR |
α-conotoxin MI | 08CON012 | α1/δsubunits |
α-conotoxin GI | 08CON005 | α/δsite |
α-conotoxin IMI | 08CON011 | α7 homomeric nAChR |
α-conotoxin GID | CON019 | Blocker of α3β2, α7 and α4β2 nAChRs |
6. 含N-甲基-D-天冬氨酸NR2B
(NMDA, NR2B containing N-methyl-D-aspartate)
Conantokin-G
选择性、特异性抑制含NR2B的NMDAR。Conantokin-G能剂量依赖性抑制Ca2+内流，抑制NMDA诱导的兴奋性中毒效应。研究表明，在小鼠皮层神经元，Conantokin-G阻滞NMDA引发的电流信号的IC50值为480 nM。
7. 作用于酸敏感离子通道(ASIC channel, Acid-Sensing Ion Channel)的毒素
Toxin name | Catalog # | Target |
APETx2 | 07APE002 | Selective blocker of ASIC3 |
Psalmotoxin1/PcTx1 | 13PCT001 | Selective blocker of ASIC1a |
Ugr9-1 | 13UGR001 | Blocker of ASIC3 |
8. 作用于瞬时受体电位(TRP channel, transient receptor potential)的毒素
Toxin name | Catalog # | Target |
GsMTx4 | 08GSM001 | TRPC, TRPA |
Vanillotoxin3 | 10VAN003 | Activator of TRPV1 |
ProTx-I | 12PTX001 | Antagonist of TRPA1 |
9. 作用于嘌呤能通道(Purinergic channel)的毒素
Purotoxin-1
选择性抑制P2X3受体。100 nM Purotoxin-1 (PT-1)选择性抑制P2X3受体通道，在大鼠DRG神经元上，使用膜片钳实验表明：PT-1对电压门控通道和TRPV1均无抑制效应。10 µM ATP和100 µM α,β Methylene-ATP浓度下Purotoxin-1对P2X3受体有选择性作用，在该ATP浓度下Purotoxin-1对P2X2和杂化二聚体P2X2/3并无激动作用。Purotoxin-1对疼痛的潜在治疗作用。
10. 作用于其它膜受体通道(Others)的毒素
Smartox Biotechnology还提供其他类型的膜受体抑制剂：
Toxin name | Catalog # | Target |
Morphiceptin | 011CAS001 | Agonist of µ-opoid receptors |
Lys-conopressin G | 11CON14 | Vasopressin-like peptide |
GsMTx4 | 08GSM001 | Mechano sensitive ion channels |
Obtustatin | 10OBT001 | Blocks the binding of α1β1 integrin to collagen IV |
Rho-Conotoxin TIA | CON022 | Blocks α1-adrenergic receptor |
公司简介
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)”。
总之，Smartox Biotechnolgy提供一系列高质量、具开创价值的多肽毒素。这些化合物在离子通道 研究中具有高的亲和性和选择性，是相应领域科学研究理想的生物毒素提供商和贴心的合作伙伴。
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