生物大分子結構與功能相互作用力

第一章：蛋白質的結構層次本文檔共86頁；當前第1頁；編輯于星期二\3點16分1,thesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins本文檔共86頁；當前第2頁；編輯于星期二\3點16分ProteinSecondaryStructure■Secondarystructureistheregulararrangementofaminoacidresiduesinasegmentofapolypeptidechain,inwhicheachresidueisspatiallyrelatedtoitsneighborsinthesameway.■Themostcommonsecondarystructuresaretheαhelix,theβ

conformation,andβ

turns.■Thesecondarystructureofapolypeptidesegmentcanbecompletelydefinediftheφand

ψanglesareknownforallaminoacidresiduesinthatsegment.本文檔共86頁；當前第3頁；編輯于星期二\3點16分10papersfromLinusPaulingandcolleaguespublishedinPNAS,1951本文檔共86頁；當前第4頁；編輯于星期二\3點16分αhelix310helixπ

helix:theoreticallypossible,butneverfoundintheproteins?sheet:parallelandanti-parallel本文檔共86頁；當前第5頁；編輯于星期二\3點16分αhelix?sheet3.613helix本文檔共86頁；當前第6頁；編輯于星期二\3點16分Parametersoffiveactualortheoreticalsecondarystructures:本文檔共86頁；當前第7頁；編輯于星期二\3點16分αhelix:

thebackboneofthepolypeptidechainisextendedintohelicalstructureWhichIsbuiltupfromonecontinuousregion.αhelix本文檔共86頁；當前第8頁；編輯于星期二\3點16分φ,ψanglepairapproximately-60°and-50°.Thelengthrangfrom4or5to44residues.Theaveragelengthisaround10residues

本文檔共86頁；當前第9頁；編輯于星期二\3點16分3.6residuesperturnwithhydrogenbondsbetweenC’=OofresiduesnandNHofresiduesn+4.Theendofαhelicesarepolarandarealmostatthesurfaceofproteinmolecules本文檔共86頁；當前第10頁；編輯于星期二\3點16分310helixπ

helix4.416helixN+53residuesperturnanda10atomsbetweenthehydrogenbonddonorandacceptor,N+3本文檔共86頁；當前第11頁；編輯于星期二\3點16分Idealizedhelices:本文檔共86頁；當前第12頁；編輯于星期二\3點16分Hydrogenbondingpatternsforfourhelices

273103.6134.414本文檔共86頁；當前第13頁；編輯于星期二\3點16分本文檔共86頁；當前第14頁；編輯于星期二\3點16分Theαhelixhasadipolemoment1.Theoveralleffectisasignificantnetdipolefortheαhelix.Thatgivesapartialpositivechargeattheaminoend

apartialnegativechargeattheCarboxylend(0.5-0.7unitcharge)2.Unitchargeateachendattractligandsofoppositecharge.PhosphategroupsfrequentlybindattheN-terminalofαhelix.Incontrast,positivechargeligandsrarelybindatC-teminal.本文檔共86頁；當前第15頁；編輯于星期二\3點16分Someaminoacidsarepreferredinαhelix:Ala(A),Glu(E),Leu(L),andMet(M)

aregoodαhelicesformers.2)

Pro(P),Gly(G),Tyr(Y)andSer(S)

areveryPoorformers3)Themostcommonlocationforanαhelixinaproteinstructureisalongtheoutsideoftheprotein,withonesidefacingthesolutionandtheothersidefacingthehydrophobicinterioroftheprotein.4)αhelicesthatacrossmembranareinaHydrophobicenvironment,mostoftheirsideChainsarehydrophobic本文檔共86頁；當前第16頁；編輯于星期二\3點16分本文檔共86頁；當前第17頁；編輯于星期二\3點16分本文檔共86頁；當前第18頁；編輯于星期二\3點16分Saccharomycescerevisiaemitochondrialthioredoxin3Baoetal.本文檔共86頁；當前第19頁；編輯于星期二\3點16分MembraneProteinJ.Deisenhofer,H.MichelScience(245):1463,1989J.Dersenhofer,O.Epp,K.Miki,R.Huber,H.Michel,Nature(318):618,1985J.Deisenhofer,O.Epp,K.Miki,R.Huber,H.Michel,J.Mol.Biol.(180):385,1984H.MichelJ.Mol.Biol.(158):567,1982FirstMembraneProteinStructure:PhotosyntheticReactionCenterofRhodopseudomonasvirdis

紅假單胞菌Complex(foursubunits)solvedin1985(1PRC)NobelChemistryPrizewasawardedtoJ.Deisenhofer,R.Huber,H.Michelin1988.本文檔共86頁；當前第20頁；編輯于星期二\3點16分1)βsheet:

thebackboneofthepolypeptidechainisextendedintoa

zigzagstructure.2)

βsheet

isbuiltupfromacombinationofseveralregionsofthepolypeptidechain.3)Thelengthrangfrom5to10residues.β

sheet本文檔共86頁；當前第21頁；編輯于星期二\3點16分本文檔共86頁；當前第22頁；編輯于星期二\3點16分Theaminoacidecanallruninthesamebiochemicaldirection,amioterminaltocarboxyterminalTheaminoacidcanhavealternatingdirections,theN-terminaltoC-terminalfollowbyC-terminaltoN-terminal本文檔共86頁；當前第23頁；編輯于星期二\3點16分Twoformshaveadistinctivepatternofhydrogen-bondingParallelAntiparallelTheβsheetthatareformedfromseveralβstrandsare

“pleated”本文檔共86頁；當前第24頁；編輯于星期二\3點16分βsheetcanalsocombineintomixedβsheet(About20%ofknownproteinstructuresaremixed)本文檔共86頁；當前第25頁；編輯于星期二\3點16分本文檔共86頁；當前第26頁；編輯于星期二\3點16分Almostalltheβsheethavetwiststrands.This

twisthasthesamehandedness

(right-handed)φ,ψangleswithinthebroadstructurallyallowedregion本文檔共86頁；當前第27頁；編輯于星期二\3點16分本文檔共86頁；當前第28頁；編輯于星期二\3點16分theDouble-headedArrowheadProteaseInhibitorA

Baoetal.本文檔共86頁；當前第29頁；編輯于星期二\3點16分本文檔共86頁；當前第30頁；編輯于星期二\3點16分LoopregionfrequentlyparticipateinformingbindingsitesandenzymeactivesitesLoopregionsareatthesurfaceofproteinmoleculesHairpinloops本文檔共86頁；當前第31頁；編輯于星期二\3點16分Hydrogenbondbetweentheoxygenof1stcarboxylgroupandhydrogenofthe4thaminogroupβ-turns:

connecttheendsoftwoadjacentsegmentsofanantiparallelβsheet.本文檔共86頁；當前第32頁；編輯于星期二\3點16分本文檔共86頁；當前第33頁；編輯于星期二\3點16分Productsof13genesinvolvedinpeptidyl-prolylcis-transisomeraseactivitythecommonpresenceofProandGlyresiduesinβturnsβ

turns本文檔共86頁；當前第34頁；編輯于星期二\3點16分

γ

turnHydrogenbondbetweentheoxygenof1stcarboxylgroupandhydrogenofthe3rdaminogroup本文檔共86頁；當前第35頁；編輯于星期二\3點16分ARamachandranplot本文檔共86頁；當前第36頁；編輯于星期二\3點16分本文檔共86頁；當前第37頁；編輯于星期二\3點16分SchematicpicturesofproteinshighlightsecondarystructureSimplifyFacilitateseeingsimilaritybetweenproteinsHelicessometimescylinders本文檔共86頁；當前第38頁；編輯于星期二\3點16分TopologydiagramsareusefulforclassificationofproteinstructuresShowthedirectionofeachβstrandandthewaythestrandsareconnectedtoeachotheralongthepolypeptidechain本文檔共86頁；當前第39頁；編輯于星期二\3點16分1,Thesecondarystructures2,Supersecondarystructuresanddomains

3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins本文檔共86頁；當前第40頁；編輯于星期二\3點16分Supersecondarystructures,alsocalledmotifsorsimplyfolds,

areparticularlystablearrangementsofseveralelementsofsecondarystructureandtheconnectionsbetweenthem.本文檔共86頁；當前第41頁；編輯于星期二\3點16分Twoαhelicesthatareconnectedbyashortloopregion.A:helix-turn-helixmotifisspecificforDNAbindingB:thecalciumbindingmotifispresentinmanyproteinsWhosefunctionisregulatedbycalcium.本文檔共86頁；當前第42頁；編輯于星期二\3點16分Thecalcium-bindingmotifissymbolizedbyrighthandExample:thecalciumisboundtothemotifinthetroponin-CThecalcium-bindingmotifissymbolizedbyarighthand.ThismotifiscalledanEFhandbecausethefifthandsixthhelicesfromtheaminoterminusinstructureOfparavalbumin(inmusclerelaxationfoundin1973)whichalabeledEandF,arepartsofthestructurethatwereoriginalusedtoillustratecalciumbindingbythismotif.Theloopregionbetweenthetwoahelicesbindsthecalciumatom.CarboxylsidechainsfromAspandGlu,main-chainC’=OandH2Ofromligandstometalatom.Thehelix-loop-helixmotifprovidesascaffoldThatholdsthecalciumligandinproperpositiontobendandreleasecalcium.c)Thestructureoftroponin-CisbuiltupfromfourEFmotifs.本文檔共86頁；當前第43頁；編輯于星期二\3點16分本文檔共86頁；當前第44頁；編輯于星期二\3點16分Hairpinβmotif(Nospecificfunction)ThestrongpreferenceforβstrandstobeadjacentinβsheetswhentheyareadjacentintheaminoacidSequenceandthustoformahairpinβmotif.Thelengthoftheloopregionbetweentheβstrandsverybutaregenerallyfrom2to5residueslong.Thereisnospecificfunctionassociatedwiththismotif.本文檔共86頁；當前第45頁；編輯于星期二\3點16分Twoexamples:a)bovintrypsininhibitor;b)snakevenomerabutoxin本文檔共86頁；當前第46頁；編輯于星期二\3點16分TheGreekkeymotifExample:theenzymeStaphylococcusnuclease,anenzymethatdegradesDNATheGreekkeymotifisnotassociatedwithanyspecificfunction,Butitoccursfrequentlyinproteinstructures.

本文檔共86頁；當前第47頁；編輯于星期二\3點16分The

β-α-βmotifcontainstwoparallelβstrandsThisloopisofteninvolvedinFormingthefunctionalbindingsite,oractivesite.Theloopregionscanbeofverydifferentlengths,from1or2residuestoover100.ThetwoloopshaveDifferentfunctions.Theloopthatconnectsthecarboxylendoftheβstrandwithaminoendofαhelixisofteninvolvedinformingthefunctionalbindingsite,oractivesite,ofthesestructures.Theseloopregionsthususuallyhaveconservedaminoacidsequencesinhomologousproteins.Incontrast,theotherloophasnotyetfoundtocontributetoanactivesite.本文檔共86頁；當前第48頁；編輯于星期二\3點16分Connectionsbetweenβstrandsinlayeredβsheets本文檔共86頁；當前第49頁；編輯于星期二\3點16分Twoarrangementsofβ

strandsstabilizedbythetendencyofthestrandstotwist.Hemolysin(apore-formingtoxinthatkillsacellbycreatingaholeinitsmembrane)fromthebacteriumStaphylococcusaureus(PDB7AHL).photolyase(aproteinthatrepairscertaintypesofDNAdamage)fromE.coli(PDB1DNP).本文檔共86頁；當前第50頁；編輯于星期二\3點16分

氨基酸順序相鄰的花樣通常在三維結構上也靠近

本文檔共86頁；當前第51頁；編輯于星期二\3點16分RNA結合蛋白(ROP)的四個-螺旋折疊為一個四螺旋束

本文檔共86頁；當前第52頁；編輯于星期二\3點16分

-螺旋的球狀折疊

本文檔共86頁；當前第53頁；編輯于星期二\3點16分

反平行的-鏈形成桶結構

本文檔共86頁；當前第54頁；編輯于星期二\3點16分上-下--回折桶結構

本文檔共86頁；當前第55頁；編輯于星期二\3點16分

反平行-結構中的希臘圖案花樣

本文檔共86頁；當前第56頁；編輯于星期二\3點16分果凍卷餅狀桶(jellyrollbarrels)

結構花樣

本文檔共86頁；當前第57頁；編輯于星期二\3點16分

/

TIM桶結構開放扭曲的/結構

本文檔共86頁；當前第58頁；編輯于星期二\3點16分開放扭曲的α/β結構中的結合部位形成裂縫

本文檔共86頁；當前第59頁；編輯于星期二\3點16分Proteinmoleculesareorganizedinastructuralhierarchy(等級）PrimarystructureSecondarystructureTertiarystructure(domains)Quaternarystructure本文檔共86頁；當前第60頁；編輯于星期二\3點16分LargepolypeptidechainsfoldintoseveraldomainsEGF:domainsthatarehomologoustoepidermal(表皮細胞）growthfactor(53aminoacids)本文檔共86頁；當前第61頁；編輯于星期二\3點16分Constructinglargemotifsfromsmallerones本文檔共86頁；當前第62頁；編輯于星期二\3點16分1,re-visitofthesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins本文檔共86頁；當前第63頁；編輯于星期二\3點16分Helpfulwebsites:1,PDB(ProteinDataBank)2,SCOP(StructuralClassificationofProteins)3,comparisonofproteinstructuresin3D本文檔共86頁；當前第64頁；編輯于星期二\3點16分A,X-raycrystallographyB,NMR(nuclearmagneticresonance)C,CD(circulardichroism)D,…本文檔共86頁；當前第65頁；編輯于星期二\3點16分Computerprograms本文檔共86頁；當前第66頁；編輯于星期二\3點16分NMRandNobelPrice:1944:I.I.Rabi,suggeststhatinformationaboutatoms'nucleicanbeobtainedbystudyingtheinternalmagnetismofprotons.Thisformsthefundamentalbasisfortoday'sresonanceimagingtechnologies1952:

PhysicistsE.Purcell(Harvard)andF.Bloch(Stanford)discoverNuclearMagneticResonance(NMR).

1991:R.Ernst,AdvancesinNMRcouldleadtotheabilitytodirectlyobservethechemicalactionofmedicationinthebody.2002:JohnB.Fenn,KoichiTanaka,KurtWüthrichforthedevelopmentofnuclearmagneticresonancespectroscopyfordeterminingthethree-dimensionalstructureofbiologicalmacromoleculesinsolution"本文檔共86頁；當前第67頁；編輯于星期二\3點16分

TheNobelPrizeinChemistry2002"forthedevelopmentofmethodsforidentificationandstructureanalysesofbiologicalmacromolecules""fortheirdevelopmentofsoftdesorptionionisationmethodsformassspectrometricanalysesofbiologicalmacromolecules""forhisdevelopmentofnuclearmagneticresonancespectroscopyfordeterminingthethree-dimensionalstructureofbiologicalmacromoleculesinsolution"

JohnB.Fenn

KoichiTanaka

KurtWüthrich

1/4oftheprize

1/4oftheprize

1/2oftheprizeUSAJapanSwitzerlandVirginiaCommonwealthUniversity

Richmond,VA,USAShimadzuCorp.

Kyoto,JapanEidgen?ssischeTechnischeHochschule(SwissFederalInstituteofTechnology)

Zurich,Switzerland;TheScrippsResearchInstitute

LaJolla,CA,USAb.1917b.1959b.1938本文檔共86頁；當前第68頁；編輯于星期二\3點16分本文檔共86頁；當前第69頁；編輯于星期二\3點16分本文檔共86頁；當前第70頁；編輯于星期二\3點16分3Dstructurecomparison:

本文檔共86頁；當前第71頁；編輯于星期二\3點16分1,re-visitofthesecondarystructures2,Toolstoinvestigatetheproteinconformation3,Supersecondarystructuresanddomains4,globularproteinsandSCOP5,fibrousproteins本文檔共86頁；當前第72頁；編輯于星期二\3點16分Inconsideringthesehigherlevelsofstructure,itisusefultoclassifyproteinsintotwomajorgroups:fibrousproteins,havingpolypeptidechainsarrangedinlongstrandsorsheets,andglobularproteins,havingpolypeptidechainsfoldedintoasphericalorglobularshape.本文檔共86頁；當前第73頁；編輯于星期二\3點16分Thetwogroupsdifferfunctionallyfromeachother:fibrousproteinsprovidesupport,shape,andexternalprotectiontovertebratesglobularproteins:mostenzymesandregulatoryproteinsThetwogroupsarestructurallydistinct:

fibrousproteinsusuallyconsistlargelyofasingletypeofsecondarystructure;globularproteinsoftencontainseveraltypesofsecondarystructure.本文檔共86頁；當前第74頁；編輯于星期二\3點16分StructuralClassificationofProteins(SCOP)(globularproteins)1,Allα2,Allβ3,α/β4,α+β本文檔共86頁；當前第75頁；編輯于星期二\3點16分Proteinfamilyandsuperfamily本文檔共86頁；當前第76頁；編輯于星期二\3點16分本文檔共86頁；當前第77頁；編輯于星期二\3點16分本文檔共86頁；當前第78頁；編輯于星期二\