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1、DOI:10.1002/cmdc.201500261FullPapersPhageSelectionofBicyclicPeptideLigandsoftheNotch1Receptor[a,b][b][a]CharlotteUrech-Varenne,FreddyRadtke,*andChristianHeinis*PreciseregulationoftheNotchsignalingpathwayiscrucial,asedfromcombinatoriallibrariesbyphagedisplay.A
2、ffinitymatu-increasesordeficienciesinsignalingareassociatedwithdis-rationyieldedligandswithdissociationconstant(Kd)valuesaseases,includingawiderangeofcancers.Recentstudieshavelowas150nm.Thebicyclicpeptidesincreasedthemeltingdemonstratedthatmonoclonalantibodie
3、sthatbindandstabi-temperatureoftheNRRbyupto88C,thussubstantiallystabi-lizethestructureofthenegativeregulatoryregion(NRR)inlizingtheproteinstructure,buttheydidnotinhibitNotchsig-theextracellulardomainoftheNotchreceptorcaninhibitnalingincellularassays.AlthoughN
4、otchsignalingcouldnotNotchsignaling.Inthiswork,weposedthequestionwhetherbeinhibited,thisworkdemonstratesthatphage-selectedbicy-bicyclicpeptides,beingaround100-foldsmallerthanantibod-clicpeptidescanstabilizeproteins;thiscapacityofbicyclicies,canalsostabilizeth
5、eNRRandinhibitNotchsignaling.Bicy-peptidesmaybeexploitedformodulatingtheconformationofclicpeptidesthatbindtheNRRofhumanNotch1wereisolat-otherdiseasetargets.IntroductionTheNotchpathwayisahighlyconservedsignalingcascade(NICD),whichmigratestothenucleusandactivat
6、esthetran-mediatedbyafamilyoffourtransmembranereceptors.ThisscriptionofitstargetgenesbybindingtothetranscriptionsignalingpathwayisinvolvedinembryonicdevelopmentandfactorCSLandco-activatorsincludingMastermind-like(MAML)[1][7]adulttissuehomeostasis.Thereceptors
7、arefirstsynthesizedprotein.assingleprecursorproteinsandthenprocessedatacleavageNotchsignalingregulatesmultiplecellularprocessesinclud-site,termedS1,byafurin-likeproteaseduringtransporttotheingcellproliferationanddifferentiationinacontext-dependentcellsurface,
8、wheretheyaredisplayedasheterodimers.Theex-manner,toassurecorrectembryonicdevelopmentandtissuetracellularpartofthereceptors,whichisinvolvedinligandhomeostasisinmultipleadultorgansystems.De
