α-conotoxinGID isaconopeptideoriginallyisolatedfromthevenomofthe Conusgeographus.Itiscomposedof19aminoacidsandisfoldedbytwodisulphidebondsconnectingCys1-Cys3 andCys2-Cys4.Basedonthenumberofaminoacidsbetweenthesecondandthethirdcysteineresidues(loopI)andthethirdandfourthcysteineresidues(loopII), α-conotoxinGID belongstotheα4/7-conotoxinfamily. α-conotoxinGID blocksselectively neuronalnicotinicacetylcholinereceptorswithIC50 valuesof3nM (α3β2nicotinicreceptors),5nM (α7) and150nM (α4β2). α-conotoxinGID isatleast1000-foldlesspotentontotheα1β1γδ,α3β4,andα4β4nicotinicreceptors. α-conotoxinGID isauniqueα4/7-conotoxinbecauseofitsABIlitytoblockbothα7andα3β2isoforms,contrarytoconotoxinPnIAorPnIBthataremoreselective.
Description:
AAsequence: Ile-Arg-Asp-Gla-Cys5-Cys6-Ser-Asn-Pro-Ala-Cys11-Arg-Val-Asn-Asn-Hyp-His-Val-Cys19-OH
Disulfidebonds:Cys5-Cys11 andCys6-Cys19
Length(aa): 19
Formula:C84H135N31O30S4
MolecularWeight:2185.45g/mol
Modifications:Gla4 aminoacid(gamma-carboxyglutamicacid)andHyp16 aminoacid(Hydroxyproline)
Appearance:Whitelyophilizedsolid
Solubility:waterandsalinebuffer
CASnumber:
Source:Synthetic
Purityrate:>95%
Reference:
Designandsynthesisofα-conotoxinGIDanaloguesasselectiveα4β2nicotinicacetylcholinereceptorantagoNISTs
Theα4β2nicotinicacetylcholinereceptor(nAChR)isanimportanttargetforcurrentlyapprovedsmokingcessationtherapeutics.However,thedevelopmentofhighlyselectiveα4β2nAChRantagonistsremainsasignificantchallenge.α-ConotoxinGIDisanantagonistofα4β2nAChRs,thoughitissignificantlymorepotenttowardtheα3β2andα7subtypes.Withthegoalofobtainingfurtherinsightsintoα-conotoxinGID/nAChRinteractionsthatcouldleadtothedesignofGIDanalogueswithimprovedaffinityforα4β2nAChRs,webuiltahomologymodeloftheGID/α4β2complexusinganX-rayco-crystalstructureofanα-conotoxin/acetylcholinebindingprotein(AChBP)complex.SeveraladditionalinteractionsthatcouldpotentiallyenhancetheaffinityofGIDforα4β2nAChRswereobservedinourmodel,whichledtothedesignandsynthesisof22GIDanalogues.Sevenanaloguesdisplayedinhibitoryactivitytowardα4β2nAChRsthatwascomparabletoGID.Significantly,bothGID[A10S]andGID[V13I]demonstratedmoderatelyimprovedselectivitytowardα4β2overα3β2whencomparedwithGID,whileGID[V18N]exhibitednomeasurableinhibitoryactivityfortheα3β2subtype,yetretainedinhibitoryactivityforα4β2.Inthisregard,GID[V18N]isthemostα4β2nAChRselectiveα-conotoxinanalogueidentifiedtodate.©2013WileyPeriodicals,Inc.Biopolymers(PeptSci)102:78-87,2014.
BanerjeeJ., etal. (2014) Designandsynthesisofα-conotoxinGIDanaloguesasselectiveα4β2nicotinicacetylcholinereceptorantagonists. Biopolymers. PMID: 24122487
InhibitionofNeuronalNicotinicAcetylcholineReceptorSubtypesbyα-ConotoxinGIDandAnalogues
Alpha-Conotoxinsaresmalldisulfide-richpeptidesfromthevenomoftheConusspeciesthattargetthenicotinicacetylcholinereceptor(nAChR).Theyarevaluablepharmacologicaltoolsandalsohavepotentialtherapeuticapplicationsparticularlyforthetreatmentofchronicpain.alpha-ConotoxinGIDisisolatedfromthevenomofConusgeographusandhasanunusualN-terminaltailsequencethathasbeenshowntobeimportantforbindingtothealpha4beta2subtypeofthenAChR.Todate,onlyfourconotoxinsthatinhibitthealpha4beta2subtypehavebeencharacterized,buttheyareofconsiderableinterestasitisthemostabundantnAChRsubtypeinthemammalianbrainandhasbeenimplicatedinarangeofdiseases.Inthisstudy,analysisofalanine-scanandtruncationmutantsofGIDrevealsthataconservedprolineinalpha-conotoxinsisimportantforactivityatthealpha7,alpha3beta2,andalpha4beta2subtypes.Althoughtheprolineresiduewasthemostcriticalresidueforactivityatthealpha3beta2subtype,Asp(3),Arg(12),andAsn(14)arealsocriticalatthealpha7subtype.Interestingly,veryfewofthemutationstestedretainedactivityatthealpha4beta2subtypeindicatingatightlydefinedbindingsite.Thislackoftolerancetosequencevariationmayexplainthelackofselectiveligandsdiscoveredforthealpha4beta2subtypetodate.Overall,ourfindingscontributetotheunderstandingofthestructure-activityrelationshipsofalpha-conotoxinsandmaybebeneficialfortheongoingattemptstoexploitmodulatorsoftheneuronalnAChRsastherapeuticagents.
MillardE., etal. (2009) InhibitionofNeuronalNicotinic AcetylcholineReceptorSubtypesby α-ConotoxinGIDandAnalogues.JBC. PMID: 19098004
Isolation,Structure,andActivityofGID,aNovel4/7-ConotoxinwithanExtendedN-terminalSequence
Usingassay-directedfractionationofConusgeographuscrudevenom,weisolatedalpha-conotoxinGID,whichactsselectivelyatneuronalnicotinicacetylcholinereceptors(nAChRs).Unlikeotherneuronallyselectivealpha-conotoxins,alpha-GIDhasafouraminoacidN-terminaltail,gamma-carboxyglutamate(Gla),andhydroxyproline(O)residues,andlacksanamidatedCterminus.GIDinhibitsalpha7andalpha3beta2nAChRswithIC(50)valuesof5and3nm,respectivelyandisatleast1000-foldlesspotentatthealpha1beta1gammadelta,alpha3beta4,andalpha4beta4combinations.GIDalsopotentlyinhibitsthealpha4beta2subtype(IC(50)of150nm).DeletionoftheN-terminalsequence(GIDDelta1-4)significantlydecreasedactivityatthealpha4beta2nAChRbuthardlyaffectedpotencyatalpha3beta2andalpha7nAChRs,despiteenhancingtheoff-ratesatthesereceptors.Incontrast,Arg(12)contributedtoalpha4beta2andalpha7activitybutnottoalpha3beta2activity.Thethree-dimensionalstructureofGIDiswelldefinedoverresidues4-19withasimilarmotiftootheralpha-conotoxins.However,despiteitsinfluenceonactivity,thetailappearstobedisorderedinsolution.ComparisonofGIDwithotheralpha4/7-conotoxinswhichpossessanNN(P/O)motifinloopII,revealedacorrelationbetweenincreasinglengthofthealiphaticside-chaininposition10(equivalentto13inGID)andgreateralpha7versusalpha3beta2selectivity.
NickeA., etal. (2003) Isolation,Structure,andActivityofGID,aNovel4/7-ConotoxinwithanExtendedN-terminalSequence. JBC. PMID: 12419800
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