生物大分子結(jié)構(gòu)與功能相互作用力

第一章：蛋白質(zhì)的結(jié)構(gòu)層次當(dāng)前1頁，總共86頁。1,thesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins當(dāng)前2頁，總共86頁。ProteinSecondaryStructure■Secondarystructureistheregulararrangementofaminoacidresiduesinasegmentofapolypeptidechain,inwhicheachresidueisspatiallyrelatedtoitsneighborsinthesameway.■Themostcommonsecondarystructuresaretheαhelix,theβ

conformation,andβ

turns.■Thesecondarystructureofapolypeptidesegmentcanbecompletelydefinediftheφand

ψanglesareknownforallaminoacidresiduesinthatsegment.當(dāng)前3頁，總共86頁。10papersfromLinusPaulingandcolleaguespublishedinPNAS,1951當(dāng)前4頁，總共86頁。αhelix310helixπ

helix:theoreticallypossible,butneverfoundintheproteins?sheet:parallelandanti-parallel當(dāng)前5頁，總共86頁。αhelix?sheet3.613helix當(dāng)前6頁，總共86頁。Parametersoffiveactualortheoreticalsecondarystructures:當(dāng)前7頁，總共86頁。αhelix:

thebackboneofthepolypeptidechainisextendedintohelicalstructureWhichIsbuiltupfromonecontinuousregion.αhelix當(dāng)前8頁，總共86頁。φ,ψanglepairapproximately-60°and-50°.Thelengthrangfrom4or5to44residues.Theaveragelengthisaround10residues

當(dāng)前9頁，總共86頁。3.6residuesperturnwithhydrogenbondsbetweenC’=OofresiduesnandNHofresiduesn+4.Theendofαhelicesarepolarandarealmostatthesurfaceofproteinmolecules當(dāng)前10頁，總共86頁。310helixπ

helix4.416helixN+53residuesperturnanda10atomsbetweenthehydrogenbonddonorandacceptor,N+3當(dāng)前11頁，總共86頁。Idealizedhelices:當(dāng)前12頁，總共86頁。Hydrogenbondingpatternsforfourhelices

273103.6134.414當(dāng)前13頁，總共86頁。當(dāng)前14頁，總共86頁。Theαhelixhasadipolemoment1.Theoveralleffectisasignificantnetdipolefortheαhelix.Thatgivesapartialpositivechargeattheaminoend

apartialnegativechargeattheCarboxylend(0.5-0.7unitcharge)2.Unitchargeateachendattractligandsofoppositecharge.PhosphategroupsfrequentlybindattheN-terminalofαhelix.Incontrast,positivechargeligandsrarelybindatC-teminal.當(dāng)前15頁，總共86頁。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當(dāng)前16頁，總共86頁。當(dāng)前17頁，總共86頁。當(dāng)前18頁，總共86頁。Saccharomycescerevisiaemitochondrialthioredoxin3Baoetal.當(dāng)前19頁，總共86頁。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.當(dāng)前20頁，總共86頁。1)βsheet:

thebackboneofthepolypeptidechainisextendedintoa

zigzagstructure.2)

βsheet

isbuiltupfromacombinationofseveralregionsofthepolypeptidechain.3)Thelengthrangfrom5to10residues.β

sheet當(dāng)前21頁，總共86頁。當(dāng)前22頁，總共86頁。Theaminoacidecanallruninthesamebiochemicaldirection,amioterminaltocarboxyterminalTheaminoacidcanhavealternatingdirections,theN-terminaltoC-terminalfollowbyC-terminaltoN-terminal當(dāng)前23頁，總共86頁。Twoformshaveadistinctivepatternofhydrogen-bondingParallelAntiparallelTheβsheetthatareformedfromseveralβstrandsare

“pleated”當(dāng)前24頁，總共86頁。βsheetcanalsocombineintomixedβsheet(About20%ofknownproteinstructuresaremixed)當(dāng)前25頁，總共86頁。當(dāng)前26頁，總共86頁。Almostalltheβsheethavetwiststrands.This

twisthasthesamehandedness

(right-handed)φ,ψangleswithinthebroadstructurallyallowedregion當(dāng)前27頁，總共86頁。當(dāng)前28頁，總共86頁。theDouble-headedArrowheadProteaseInhibitorA

Baoetal.當(dāng)前29頁，總共86頁。當(dāng)前30頁，總共86頁。LoopregionfrequentlyparticipateinformingbindingsitesandenzymeactivesitesLoopregionsareatthesurfaceofproteinmoleculesHairpinloops當(dāng)前31頁，總共86頁。Hydrogenbondbetweentheoxygenof1stcarboxylgroupandhydrogenofthe4thaminogroupβ-turns:

connecttheendsoftwoadjacentsegmentsofanantiparallelβsheet.當(dāng)前32頁，總共86頁。當(dāng)前33頁，總共86頁。Productsof13genesinvolvedinpeptidyl-prolylcis-transisomeraseactivitythecommonpresenceofProandGlyresiduesinβturnsβ

turns當(dāng)前34頁，總共86頁。

γ

turnHydrogenbondbetweentheoxygenof1stcarboxylgroupandhydrogenofthe3rdaminogroup當(dāng)前35頁，總共86頁。ARamachandranplot當(dāng)前36頁，總共86頁。當(dāng)前37頁，總共86頁。SchematicpicturesofproteinshighlightsecondarystructureSimplifyFacilitateseeingsimilaritybetweenproteinsHelicessometimescylinders當(dāng)前38頁，總共86頁。TopologydiagramsareusefulforclassificationofproteinstructuresShowthedirectionofeachβstrandandthewaythestrandsareconnectedtoeachotheralongthepolypeptidechain當(dāng)前39頁，總共86頁。1,Thesecondarystructures2,Supersecondarystructuresanddomains

3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins當(dāng)前40頁，總共86頁。Supersecondarystructures,alsocalledmotifsorsimplyfolds,

areparticularlystablearrangementsofseveralelementsofsecondarystructureandtheconnectionsbetweenthem.當(dāng)前41頁，總共86頁。Twoαhelicesthatareconnectedbyashortloopregion.A:helix-turn-helixmotifisspecificforDNAbindingB:thecalciumbindingmotifispresentinmanyproteinsWhosefunctionisregulatedbycalcium.當(dāng)前42頁，總共86頁。Thecalcium-bindingmotifissymbolizedbyrighthandExample:thecalciumisboundtothemotifinthetroponin-CThecalcium-bindingmotifissymbolizedbyarighthand.ThismotifiscalledanEFhandbecausethefifthandsixthhelicesfromtheaminoterminusinstructureOfparavalbumin(inmusclerelaxationfoundin1973)whichalabeledEandF,arepartsofthestructurethatwereoriginalusedtoillustratecalciumbindingbythismotif.Theloopregionbetweenthetwoahelicesbindsthecalciumatom.CarboxylsidechainsfromAspandGlu,main-chainC’=OandH2Ofromligandstometalatom.Thehelix-loop-helixmotifprovidesascaffoldThatholdsthecalciumligandinproperpositiontobendandreleasecalcium.c)Thestructureoftroponin-CisbuiltupfromfourEFmotifs.當(dāng)前43頁，總共86頁。當(dāng)前44頁，總共86頁。Hairpinβmotif(Nospecificfunction)ThestrongpreferenceforβstrandstobeadjacentinβsheetswhentheyareadjacentintheaminoacidSequenceandthustoformahairpinβmotif.Thelengthoftheloopregionbetweentheβstrandsverybutaregenerallyfrom2to5residueslong.Thereisnospecificfunctionassociatedwiththismotif.當(dāng)前45頁，總共86頁。Twoexamples:a)bovintrypsininhibitor;b)snakevenomerabutoxin當(dāng)前46頁，總共86頁。TheGreekkeymotifExample:theenzymeStaphylococcusnuclease,anenzymethatdegradesDNATheGreekkeymotifisnotassociatedwithanyspecificfunction,Butitoccursfrequentlyinproteinstructures.

當(dāng)前47頁，總共86頁。The

β-α-βmotifcontainstwoparallelβstrandsThisloopisofteninvolvedinFormingthefunctionalbindingsite,oractivesite.Theloopregionscanbeofverydifferentlengths,from1or2residuestoover100.ThetwoloopshaveDifferentfunctions.Theloopthatconnectsthecarboxylendoftheβstrandwithaminoendofαhelixisofteninvolvedinformingthefunctionalbindingsite,oractivesite,ofthesestructures.Theseloopregionsthususuallyhaveconservedaminoacidsequencesinhomologousproteins.Incontrast,theotherloophasnotyetfoundtocontributetoanactivesite.當(dāng)前48頁，總共86頁。Connectionsbetweenβstrandsinlayeredβsheets當(dāng)前49頁，總共86頁。Twoarrangementsofβ

strandsstabilizedbythetendencyofthestrandstotwist.Hemolysin(apore-formingtoxinthatkillsacellbycreatingaholeinitsmembrane)fromthebacteriumStaphylococcusaureus(PDB7AHL).photolyase(aproteinthatrepairscertaintypesofDNAdamage)fromE.coli(PDB1DNP).當(dāng)前50頁，總共86頁。

氨基酸順序相鄰的花樣通常在三維結(jié)構(gòu)上也靠近

當(dāng)前51頁，總共86頁。RNA結(jié)合蛋白(ROP)的四個-螺旋折疊為一個四螺旋束

當(dāng)前52頁，總共86頁。

-螺旋的球狀折疊

當(dāng)前53頁，總共86頁。

反平行的-鏈形成桶結(jié)構(gòu)

當(dāng)前54頁，總共86頁。上-下--回折桶結(jié)構(gòu)

當(dāng)前55頁，總共86頁。

反平行-結(jié)構(gòu)中的希臘圖案花樣

當(dāng)前56頁，總共86頁。果凍卷餅狀桶(jellyrollbarrels)

結(jié)構(gòu)花樣

當(dāng)前57頁，總共86頁。

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TIM桶結(jié)構(gòu)開放扭曲的/結(jié)構(gòu)

當(dāng)前58頁，總共86頁。開放扭曲的α/β結(jié)構(gòu)中的結(jié)合部位形成裂縫

當(dāng)前59頁，總共86頁。Proteinmoleculesareorganizedinastructuralhierarchy(等級）PrimarystructureSecondarystructureTertiarystructure(domains)Quaternarystructure當(dāng)前60頁，總共86頁。LargepolypeptidechainsfoldintoseveraldomainsEGF:domainsthatarehomologoustoepidermal(表皮細(xì)胞）growthfactor(53aminoacids)當(dāng)前61頁，總共86頁。Constructinglargemotifsfromsmallerones當(dāng)前62頁，總共86頁。1,re-visitofthesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins當(dāng)前63頁，總共86頁。Helpfulwebsites:1,PDB(ProteinDataBank)2,SCOP(StructuralClassificationofProteins)3,comparisonofproteinstructuresin3D當(dāng)前64頁，總共86頁。A,X-raycrystallographyB,NMR(nuclearmagneticresonance)C,CD(circulardichroism)D,…當(dāng)前65頁，總共86頁。Computerprograms當(dāng)前66頁，總共86頁。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"當(dāng)前67頁，總共86頁。

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當(dāng)前68頁，總共86頁。當(dāng)前69頁，總共86頁。當(dāng)前70頁，總共86頁。3Dstructurecomparison:

當(dāng)前71頁，總共86頁。1,re-visitofthesecondarystructures2,Toolstoinvestigatetheproteinconformation3,Supersecondarystructuresanddomains4,globularproteinsandSCOP5,fibrousproteins當(dāng)前72頁，總共86頁。Inconsideringthesehigherlevelsofstructure,itisusefultoclassifyproteinsintotwomajorgroups:fibrousproteins,havingpolypeptidechainsarrangedinlongstrandsorsheets,andglobularproteins,havingpolypeptidechainsfoldedintoasphericalorglobularshape.當(dāng)前73頁，總共86頁。Thetwogroupsdifferfunctionallyfromeachother:fibrousproteinsprovidesupport,shape,andexternalprotectiontovertebratesglobularproteins:mostenzymesandregulatoryproteinsThetwogroupsarestructurallydistinct:

fibrousproteinsusuallyconsistlargelyofasingletypeofsecondarystructure;globularproteinsoftencontainseveraltypesofsecondarystructure.當(dāng)前74頁，總共86頁。StructuralClassificationofProteins(SCOP)(globularproteins)1,Allα2,Allβ3,α/β4,α+β當(dāng)前75頁，總共86頁。Proteinfamilyandsuperfamily當(dāng)前76頁，總共86頁。當(dāng)前77頁，總共86頁。當(dāng)前78頁，總共86頁。α/