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Smartox/α7 nAChR selective blocker/08CON011-00500/0.5mg
α-conotoxinIMI (alpha-conotoxinIMI)isaconopeptidethathasbeenisolatedfromthevenomoftheconesnailConusimperialis. α-conotoxinIMI actsonpostsynapticmembranes,andbindsontoandinhibitsnicotinicacetylcholinereceptors(nAChR). α-conotoxinIMI isaselectiveblockerof α7homomericnicotinicacetylcholinereceptors (IC50 ~200nM).IthasnoeffectonnAChRscomposedofα2/ß2,α3/ß2,α4/ß2,α2/ß4,α3/ß4,orα4/ß4subunits. α-conotoxinsIMI actsindependentlyofvoltagevalue.Thistoxinishighlyactiveagainsttheneuromuscularreceptorinfrog.
Description:
AAsequence: Gly-Cys2-Cys3-Ser-Asp-Pro-Arg-Cys8-Ala-Trp-Arg-Cys12-NH2
Disulfidebonds: Cys2-Cys8 andCys3-Cys12
Length(aa): 12
Formula: C52H78N20O15S4
MolecularWeight: 1352.92Da
Appearance: Whitelyophilizedsolid
Solubility: waterorsalinebuffer
CASnumber: [156467-85-5]Source: Synthetic
Purityrate: >95%
Reference:
Alpha-conotoxinsImIandImII.Similaralpha7nicotinicreceptorantagoNISTsactatdifferentsites
Anovelconotoxin,alpha-conotoxinImII(alpha-CTxImII),identifiedfromConusimperialisvenomducts,waschemicallysynthesized.ApreviouslycharacterizedC.imperialisconotoxin,alpha-conotoxinImI(alpha-CTxImI),iscloselyrelated;9of12aminoacidsareidentical.Bothalpha-CTxImIIandalpha-CTxImIfunctionallyinhibitheterologouslyexpressedratalpha7nAChRswithsimilarIC(50)values.FurThermore,theBIOLOGicalactivitiesofintracraniallyappliedalpha-CTxImIandalpha-CTxImIIaresimilaroverthesamedosagerange,andareconsistentwithalpha7nAChRinhibition.However,unlikealpha-CTxImI,alpha-CTxImIIwasnotabletoblockthebindingofalpha-bungarotoxintoalpha7nAChRs.alpha-ConotoxinImIandalpha-bungarotoxin-bindingsiteshavebeenwellcharacterizedasoverlappingandlocatedatthecleftbetweenadjacentnAChRsubunits.Becausealpha-CTxImIandalpha-CTxImIIshareextensivesequencehomology,theinABIlityofalpha-CTxImIItocompetewithalpha-BgTxissurprising.Furthermore,functionalstudiesinoocytesindicatethatthereisnooverlapbetweenfunctionalbindingsitesofalpha-CTxImIandalpha-CTxImII.Likealpha-CTxImI,theblockbyalpha-CTxImIIisvoltage-independent.Thus,alpha-CTxImIIrepresentsaprobeforanovelantagonistbindingsite,ormicrosite,onthealpha7nAChR.
Ellison,M., etal. (2003)Alpha-conotoxinsImIandImII.Similaralpha7nicotinicreceptorantagonistsactatdifferentsites, JBiolChem. PMID: 12384509
Structure-activityrelationshipsinapeptidicalpha7nicotinicacetylcholinereceptorantagonist
Alpha-Conotoxinsaresmalldisulfide-constrainedpeptidetoxinswhichactasantagonistsatspecificsubtypesofnicotinicacetylcholinereceptors(nAChreceptors).Inthisstudy,weanalyzedthestructuresandactivitiesofthreemutantsofalpha-conotoxinImI,a12aminoacidpeptideactiveatalpha7nAChreceptors,inordertogaininsightintotheprimaryandtertiarystructuralrequirementsofneuronalalpha-conotoxinspecificity.NMRsolutionstructuresweredeterminedformutantsR11E,R7L,andD5N,resultinginrepresentativeensemblesof20conformerswithaveragepairwiseRMSDvaluesof0.46,0.52,and0.62Afromtheirmeanstructures,respectively,forthebackboneatomsN,C(alpha),andC’ofresidues2-11.TheR11Emutantwasfoundtohaveactivitynearthatofwild-typeImI,whileR7LandD5Ndemonstratedactivitiesreducedbyatleasttwoordersofmagnitude.Comparisonofthestructuresrevealsacommontwo-looparchitecture,withvariationsobservedinbackboneandside-chaindihedralanglesaswellassurfaceelectrostaticpotentialsuponmutation.Correlationofthesestructuresandactivitieswiththosefrompreviouslypublishedstudiesemphasizesthatexistinghypothesesregardingthemoleculardeterminantsofalpha-conotoxinspecificityarenotadequateforexplainingpeptideactivity,andsuggeststhatmoresubtlefeatures,visualizedhereattheatomiclevel,areimportantforreceptorbinding.Thesedata,inconjunctionwithreportedcharacterizationsoftheacetylcholinebindingsite,supportamodeloftoxinactivityinwhichasinglesolvent-accessIBLetoxinside-chainanchorsthecomplex,withsupportingweakinteractionsdeterminingboththeefficacyandthesubtypespecificityoftheinhibitoryactivity.
Rogers,J.P., etal.(2000)Structure-activityrelationshipsinapeptidicalpha7nicotinicacetylcholinereceptorantagonist, JMolBiol. PMID: 11124036
alpha-ConotoxinImIexhibitssubtype-specificnicotinicacetylcholinereceptorblockade:preferentialinhibitionofhomomericalpha7andalpha9receptors
Throughastudyofcloned nicotinic receptorsexpressedinXenopusoocytes,weprovideevidencethat alpha-conotoxin ImI,apeptidemarinesnailtoxinthatinducesseizuresinrodents,selectivelyblockssubtypesof nicotinic acetylcholine receptors. alpha-Conotoxin ImI blocks homomeric alpha 7nicotinic receptorswiththehighestapparentaffinityand homomeric alpha 9receptorswith8-foldloweraffinity.Thistoxinhasnoeffectonreceptorscomposedof alpha 2beta2, alpha 3beta2, alpha 4beta2, alpha 2beta4, alpha 3beta4,or alpha 4beta4subunitcombinations.Incontrasttoalpha-bungarotoxin,whichhashighaffinityfor alpha 7, alpha 9,and alpha 1beta1gammadeltareceptors, alpha-conotoxin ImI haslowaffinityforthemusclenAChR.RelatedConuspeptides, alpha-conotoxinsMIandGI,exhibitadistinctspecificity,strictlytargetingthemusclesubtype receptor butnotalpha 7or alpha 9receptors. alpha-Conotoxinsthusrepresentselectivetoolsforthestudyofneuronal nicotinic acetylcholine receptors.
Johnson,D.S., etal. (1995)Alpha-ConotoxinImIexhibitssubtype-specificnicotinicacetylcholinereceptorblockade:preferentialinhibitionofhomomericalpha7andalpha9receptors, MolPharmacol. PMID: 7651351
Anicotinicacetylcholinereceptorligandofuniquespecificity,alpha-conotoxinImI
Wereporttheisolation,characterization,andtotalsynthesisofasmallpeptideligandfornicotinicacetylcholinereceptors(nAChRs).Itishighlyactiveagainsttheneuromuscularreceptorinfrogbutnotinmice.Incontrast,itinducesseizureswheninjectedcentrallyinmiceandrats,suggestingthatitmaytargetneuronalnAChRsinmammals.Althoughsuchreceptorsmaybeimportantinbothnormalcognitionandthepathophysiologyofseveralneuropsychiatricdisorders,therearefewligandstodiscriminatebetweenthemultiplereceptorsubtypes.Thenewpeptideisahighlydivergentalpha-conotoxinfromthesnailConusimperialis,whichpreysonpolychaeteworms.Inthisarticle,thepurification,structuralanalysis,synthesis,andpreliminaryphysiologicalcharacterizationofalpha-conotoxinImI(alpha-CTx-ImI)arereported.Thesequenceofthepeptideis:Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2.Thepeptideshowsstrikingsequencedifferencesfromallalpha-conotoxinsoffish-huntingConus,butitsdisulfide-bridgingissimilar:[2-8;3-12].WesuggestthatconevenomsmayprovideanarrayofligandswithselectivityforvariousneuronalnAChRsubtypes.
McIntosh,J.M., etal. (1994)Anicotinicacetylcholinereceptorligandofuniquespecificity,alpha-conotoxinImI, J BiolChem. PMID: 8206995
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