中山大学生物化学课件.ppt
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中山大学生物化学课件.ppt
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liguofu,4ProteinFunction,4.1Generalfeatures4.2Oxygen-bindingproteins4.3Immunoglobulins4.4Musclecontraction,liguofu,4.1Generalfeatures,VersatileinfunctionBeinghardtostudyFunctionviainteraction,Theinteractionwithothermolecule(ligand)isreversible.Theinterfacebetweenthebindingsiteiscomplementaryinstructure,makingsuchinteractionhighlyspecific.Structuredynamicnessofaproteinisusuallyessentialforsuchinteractions.,liguofu,4.1Generalfeatures4.2Oxygen-bindingproteins4.3Immunoglobulins4.4Musclecontraction,4ProteinFunction,liguofu,Quantitativedescriptionofinteraction
(1),Protein+nLigandPLn,liguofu,Quantitativedescriptionofinteraction
(2),Ifkdisconstant,liguofu,Quantitativedescriptionofinteraction(3),Ifkdisnotconstant,liguofu,Quantitativedescriptionofinteraction(4),liguofu,Quantitativedescriptionofinteraction(5),liguofu,Theiron-porphyrininhemoglobinaccountsfortheredcolorofblood,thecopper-porphyrininhemocyaninforbluecolorofblood,andthemagnesium-porphyrininchlorophyllisresponsibleforthegreenofplants.,liguofu,StructureofPorphyrin,Pyrrolering,Methenebridge,liguofu,Oxygencanbeboundtoaheme
(1),Heme=ProtoporphyrinIX+Fe2+,NoneoftheaasidechainsinproteinsissuitedforreversiblebindingO2,Hemeprostheticgroup,Transitionmetals,Fe&Cu,haveastrongtendencytobindO2,need,more,commonly,liguofu,Oxygencanbeboundtoaheme
(2),Heme=ProtoporphyrinIX+Fe2+,FreeIronpromotestheformationofhighlyreactiveoxygenspeciessuchashydroxylradicals.CoordinatedNatomshelppreventtheconversionofFe2+toFe3+,liguofu,Mbhasasinglebindingsiteforoxygen,Myoglobin:
153residues,16700Da,His93/F8,His64/E7,liguofu,Oxygencanbeboundtoaheme(3),Infreehememolecules,reactionofoxygenatoneofthetwo“open”coordinationbondsofironcanresultinirreversibleconversionofFe2+toFe3+Inheme-containingproteins,thisreactionispreventedbysequesteringthehemedeepwithinaproteinstructurewhereacesstothetwo“open”coordinationbondsisrestricted.Oneofthesetwocoordinationbondsisoccupiedbyaside-chainNofaHisresidue.,NOCO,Also,liguofu,QuantitativedescriptionofMbbindingO2,liguofu,Proteinstructureaffectsligandsbind
(1),Infreeheme,or,Inmyoglobin,Infreeheme,Inmyoglobinheme,or,liguofu,“Breathing”:
Molecularmotions,ThebindingofO2tohemeinmyoglobindependsonits“breathing”,Inmyoglobin,Proteinstructureaffectsligandsbind
(2),liguofu,Hbisthemost-studiedandbest-understoodprotein,Hemoglobinwasthefirstproteintobecrystallized(in1849);thefirsttobeassociatedwithaspecificphysiologicalfunction(around1875);oneofthefirstproteinstohaveitsmolecularweightdeterminedcorrectly(64,500);thefirsteukaryoticmessenger(mRNA)tobeisolatedandsubsequentlysequenced.thefirsteukaryoticproteintobesynthesizedinacell-freesysteminvitro;thesecondproteinhavingits3-Dstructuredetermined(1969).,liguofu,The“redcoloringmatter”(hemoglobin)ofanimalbloodcouldbebroughttocrystallization,withcrystalformscharacteristicoftheirbiologicalorigins(1840s-1860s).Reversibleinterconversionofoxyhemoglobinanddeoxyhemoglobinwasrevealedbyusingspectroscope(1860s).Treatmentofhemoglobinwithacidgaveacolorlessalbuminoidconstituent(globin)andarediron-containingmaterial(by1870).Thestructureofhemewaselucidatedtobeatetrapyrrol(porphyrin)derivativebychemicalsynthesis(HansFischer,1929).Similartetrapyrrolderivativesarealsousedasprostheticgroupsofotherproteins(e.g.,thecytochromesthatfunctioninbiologicaloxidationandphotosynthesis!
liguofu,Hbhasfoursubunits,Mr=64,500,141residues,146residues,liguofu,Hbsubunitsarestructurallysimilartomyoglobin,subunitlackstheshortDhelix,Dhelix,liguofu,conservedinallknownglobins,conserved,27positionsareidentical,18%,82,143,liguofu,30residues,Interactionsinthefoursubunits,19residues,19residues,HydrophobicinteractionsHbondsSaltbonds,liguofu,ThisiscalledTensestate(deoxyHb),Someionpairsarenotshownhere,Ionpairsatthe1/2and2/1interface
(1),liguofu,Ionpairsatthe1/2and2/1interface
(2),IonpairsstabilizetheTstateofdeoxyHb,liguofu,QuantitativedescriptionofHbbindingO2
(1),liguofu,Hillplot,nH:
hillcoefficient,QuantitativedescriptionofHbbindingO2(3),liguofu,HbundergoesastructuralchangeonbindingO2
(1),TensestateismorestableandthusthepredominantconformationofdeoxyHb,RelaxedstateisthepredominantconformationofhigheraffinitytoO2,BindingO2,ValE11,liguofu,IntheTstate,theporphyrinisslightlypuckered,causingthehemeirontoprotrudesomewhatontheproximalHis(HisF8)side.ThebindingofO2causesthehemetoassumeamoreplanarconformation,shiftingthepositionofHisF8andFhelix.,HbundergoesastructuralchangeonbindingO2
(2),liguofu,Allostericproteinisoneinwhichthebindingofaligandtoonesiteaffectsthebindingpropertiesofanothersiteonthesameprotein.Modulatorisamoleculethatbindstoanallostericproteinandaffectsitsbindingproperties.Homotropic:
thenormalligandandmodulatorareidentical.Heterotropic:
thenormalligandandmodulatorarenotidentical.Someproteinshavetwoormoremodulatorsandthereforecanhavebothhomotropicandheterotropicinteractions.,Hemoglobinbindsoxygencooperatively,liguofu,Twomodelforcooperativebinding,ConcertedModelMWCModel,SequentialModel,liguofu,HemoglobintransportsCO2,carbonicanhydrase,15%to20%,80%to85%,liguofu,HemoglobinalsotransportsH+,Bohreffect,H+bindsto:
NHofHis146inb4N-terminalNH2Others:
Arg,Lys,liguofu,O2bindingtoHbisregulatedbyBPG
(1),liguofu,O2bindingtoHbisregulatedbyBPG
(2),liguofu,BindingofBPGtodeoxy-HbstabilizestheT-state,thuslowerstheO2affinityofHb.,OnlyoneBPGbindstoeachdeoxy-Hbtetramer,TheBPGbindingpocketexistsintheT-state,butdisappearsintheR-stateofHb.,T-state(deoxy-Hb),R-state(oxy-Hb),PositivelychargedgroupsthatBPGinteractswith,Infetushemoglobin(a2g2),theconversionofb-His143tog-ser143resultsinthedecreaseoftheaffinityofBPG,liguofu,MutantHbsprovidedauniqueopportunitytostudystructure-functionrelationshipsinproteins,Many(500)Hbgeneticvariants,mostly(95%)withasingleaminoaciddifference,havebeenidentifiedinthehumanpopulation.Mostofsuchvariationhaveaveryminoreffectontheproteinstructureandfunction.Somedocausedebilitatingdiseases(e.g.,thosefromsicklecellanemia.)Deleteriousmutationsaremostlyclusteredaboutthehemepocketsandinthevicinityofthea-bcontactregionthatisimportantintheallosterictransition.,liguofu,Distributionofmutationsinhumanhemoglobin,GluVal,Sicklecellanemia,liguofu,liguofu,Sicklecellanemiaiscausedbyasingleaminoacidreplacementonthebsubunit:
Glu6Val,liguofu,GluVal,liguofu,liguofu,Electronmicrographofdeoxy-HbSfibersspillingoutofarupturederythrocyte.,Thesickledcellsarefragile.Theirbreakdownleadstoananemiathatleavesthevictimsusceptibletoinfectionsanddiseases.,liguofu,Theelongatedcellstendtoblockcapillaries,causinginflammationandconsiderablepain,liguofu,ByLinusPaulingin1949.,1903,1987,Normal,Trait,Patient,(Normal),(defective),liguofu,TheHbSalleleconfersasmallbutsignificantresistancetomalariainheterozygousindividuals,TheHbSallele(i.e.,sicklecelltrait)wasfoundcommonincertainpartsofAfrica.Plasmodium(aprotozoancausingmalaria)increasestheacidityoferythrocyte,favoringtheformationofdeoxy-HbS(theBohreffect),thusprobablyallowingthespleentopreferentiallyremovetheinfectedredcells.,liguofu,4.1Generalfeatures4.2Oxygen-bindingproteins4.3Immunoglobulins4.4Musclecontraction,4ProteinFunction,liguofu,liguofu,Structureofimmunoglobulin
(1),liguofu,Structureofimmunoglobulin
(2),H=HeavychainL=LightchainC=ConstantV=VariableCHO=carbohydrate,liguofu,Structureofimmunoglobulin(3),liguofu,StructureofVariableRegion
(1),LightChain,HeavyChain,CDRs:
complementarity-determiningregionsHypervariableloops,liguofu,StructureofVariableRegion
(2),HeavyChain,liguofu,Antibodybindtightly&specificallytoantigen
(1),Smallantigen,liguofu,Smallantigen,Antibodybindtightly&specificallytoantigen
(2),Largeantigen:
lysozyme,AntibodyI,AntibodyII,V,C1,liguofu,liguofu,Fiveclassesofimmunoglobulins
(1),liguofu,liguofu,抗体的作用:
例,liguofu,Polyclonal/Monoclonalantibody,liguofu,liguofu,4.1Generalfeatures4.2Oxygen-bindingproteins4.3Immuneproteins4.4Musclecontraction,4ProteinFunction,liguofu,Musclestructure,liguofu,Musclestructure,liguofu,Musclecontraction,liguofu,Musclecontraction,liguofu,Actinmolecules,Tropomyosinmolecules,Troponinmolecules,Crossbridges(headgroupsofmyosinmolecules),Actin,Tropomyosin,Troponin,Myosinmolecule,headgroups,Splitbypapain,Thinfilament,Thinfilament,Thickfilament,liguofu,Myosin
(1),325nm,liguofu,Myosin
(2),liguofu,Myosin(3):
S1structure,liguofu,Myosin(3):
S1structure,liguofu,GactinFactin
(1),liguofu,GactinFactin
(2),liguofu,GactinFactin(3),liguofu,InteractionbetweenmyosinandF-actin,liguofu,Step1,Step2,The“powerstroke”modelofmusclecontraction,(ATP-consumingMotor),Twoconformationsofthecross-bridgeweredetectedininsectmuscle(1965),liguofu,Step3,Step4,Step1,liguofu,Tropomyosin:
lyingalongthegrooveintheF-actinhelix.Troponin:
TnC,TnI,TnTTnC:
theCa2+bindingsubunitTnI:
theinhibitorysubunitTnT:
theTm-bindingsubunitTm&TninhibitthebindingofmyosinheadstoactinunlessCa2+isabout10-5M.Inrestingmuscle,Ca2+isabout10-7M.,Theinteractionbetweenactinandmyosinareregulatedmainlybytropomyosinandtroponin.,liguofu,Tropomyosin:
coiled-coil,liguofu,Troponin
(1),TnC:
redTnI:
lightblueTnCbindingregion:
blueTnT:
yellowBoundCa2+:
blackRH:
regulatoryheadITarm:
TnI-TnTarm,liguofu,Troponin
(2),C-TnI:
C-te
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