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1、THEJOURNALOFBIOLOGICALCHEMISTRYVOL.287,NO.11,pp.8613–8620,March9,2012©2012byTheAmericanSocietyforBiochemistryandMolecularBiology,Inc.PublishedintheU.S.A.RecognitionofHumanTumorNecrosisFactor(TNF-)byTherapeuticAntibodyFragmentENERGETICSANDSTRUCTURALFEATURES*□SReceivedforpublication,
2、October28,2011,andinrevisedform,January6,2012Published,JBCPapersinPress,January19,2012,DOI10.1074/jbc.M111.318451‡§1‡§§‡‡2JakaMarusˇicˇ,CˇrtomirPodlipnik,SimonaJevsˇevar,DragoKuzman,GorazdVesnaver,andJurijLah‡§FromtheFacultyofChemistryandChemicalTechnology,UniversityofLjubljana,Asˇke
3、rcˇeva5,1000LjubljanaandSandozBiopharmaceuticals,Mengesˇ,LekPharmaceuticalsd.d.,Kolodvorska27,SI-1234Mengesˇ,SloveniaBackground:HumanTNF-isacytokineinvolvedinmanydisease-relatedcellularprocesses.Results:Highaffinitybindingoftherapeuticantibody(inhibitor)tonativeandmoltenglobule-like
4、TNF-conformationisdrivenbyspecificnoncovalentinteractions.Conclusion:Binding-coupledconformationalchangesarecrucialforantibody-TNF-recognition.Significance:ThisworkhelpslearnwhichforcesdriveunfoldingofTNF-anditsrecognitionbymonoclonalantibodiesandhowtheyaffectTNF-activityregulati
5、on.Humantumornecrosisfactor(TNF-)existsinitsfunc-humanorganism,particularlyininflammationandcellulartionalstateasahomotrimericproteinandisinvolvedininflam-immuneresponse(1–3).Itswideroleinbiologicalprocessesmationprocessesandimmuneresponseofahumanorganism.andobservationsofitsabilit
6、ytotriggerregressionoftumorsOverproductionofTNF-resultsinthedevelopmentofchronicmakestheTNF-oneofthemostintensivelyinvestigatedpro-autoimmunediseasesthatcanbesuccessfullytreatedbyinhib-teinsoverpastdecades,althoughcytotoxicitypreventsitsitorssuchasmonoclonalantibodies.However,thena
7、tureofextensiveclinicaluse(1,4).Thecrystalstructuredeterminedinantibody-TNF-recognitionremainselusiveduetoinsufficient1989(PDBcode1TNF)suggeststhatTNF-consistsofthreeunderstandingofitsmoleculardrivingforces.Therefore,weidentical17.35-kDapoly-peptidechains.Eachofthemisstudiedtheener
8、geticsofbind
