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(yè)，總共86頁(yè)。1,thesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins當(dāng)前2頁(yè)，總共86頁(yè)。ProteinSecondaryStructure■Secondarystructureistheregulararrangementofaminoacidresiduesinasegmentofapolypeptidechain,inwhicheachresidueisspatiallyrelatedtoitsneighborsinthesameway.■Themostcommonsecondarystructuresaretheαhelix,theβ

conformation,andβ

turns.■Thesecondarystructureofapolypeptidesegmentcanbecompletelydefinediftheφand

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

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

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

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

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

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

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

thebackboneofthepolypeptidechainisextendedintoa

zigzagstructure.2)

βsheet

isbuiltupfromacombinationofseveralregionsofthepolypeptidechain.3)Thelengthrangfrom5to10residues.β

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

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

twisthasthesamehandedness

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

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

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

turns當(dāng)前34頁(yè)，總共86頁(yè)。

γ

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

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

areparticularlystablearrangementsofseveralelementsofsecondarystructureandtheconnectionsbetweenthem.當(dāng)前41頁(yè)，總共86頁(yè)。Twoαhelicesthatareconnectedbyashortloopregion.A:helix-turn-helixmotifisspecificforDNAbindingB:thecalciumbindingmotifispresentinmanyproteinsWhosefunctionisregulatedbycalcium.當(dāng)前42頁(yè)，總共86頁(yè)。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(yè)，總共86頁(yè)。當(dāng)前44頁(yè)，總共86頁(yè)。Hairpinβmotif(Nospecificfunction)ThestrongpreferenceforβstrandstobeadjacentinβsheetswhentheyareadjacentintheaminoacidSequenceandthustoformahairpinβmotif.Thelengthoftheloopregionbetweentheβstrandsverybutaregenerallyfrom2to5residueslong.Thereisnospecificfunctionassociatedwiththismotif.當(dāng)前45頁(yè)，總共86頁(yè)。Twoexamples:a)bovintrypsininhibitor;b)snakevenomerabutoxin當(dāng)前46頁(yè)，總共86頁(yè)。TheGreekkeymotifExample:theenzymeStaphylococcusnuclease,anenzymethatdegradesDNATheGreekkeymotifisnotassociatedwithanyspecificfunction,Butitoccursfrequentlyinproteinstructures.

當(dāng)前47頁(yè)，總共86頁(yè)。The

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

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

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(yè)，總共86頁(yè)。RNA結(jié)合蛋白(ROP)的四個(gè)-螺旋折疊為一個(gè)四螺旋束

當(dāng)前52頁(yè)，總共86頁(yè)。

-螺旋的球狀折疊

當(dāng)前53頁(yè)，總共86頁(yè)。

反平行的-鏈形成桶結(jié)構(gòu)

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

當(dāng)前55頁(yè)，總共86頁(yè)。

反平行-結(jié)構(gòu)中的希臘圖案花樣

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

結(jié)構(gòu)花樣

當(dāng)前57頁(yè)，總共86頁(yè)。

/

TIM桶結(jié)構(gòu)開(kāi)放扭曲的/結(jié)構(gòu)

當(dāng)前58頁(yè)，總共86頁(yè)。開(kāi)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(yè)，總共86頁(yè)。Proteinmoleculesareorganizedinastructuralhierarchy(等級(jí)）PrimarystructureSecondarystructureTertiarystructure(domains)Quaternarystructure當(dāng)前60頁(yè)，總共86頁(yè)。LargepolypeptidechainsfoldintoseveraldomainsEGF:domainsthatarehomologoustoepidermal(表皮細(xì)胞）growthfactor(53aminoacids)當(dāng)前61頁(yè)，總共86頁(yè)。Constructinglargemotifsfromsmallerones當(dāng)前62頁(yè)，總共86頁(yè)。1,re-visitofthesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins當(dāng)前63頁(yè)，總共86頁(yè)。Helpfulwebsites:1,PDB(ProteinDataBank)2,SCOP(StructuralClassificationofProteins)3,comparisonofproteinstructuresin3D當(dāng)前64頁(yè)，總共86頁(yè)。A,X-raycrystallographyB,NMR(nuclearmagneticresonance)C,CD(circulardichroism)D,…當(dāng)前65頁(yè)，總共86頁(yè)。Computerprograms當(dāng)前66頁(yè)，總共86頁(yè)。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(yè)，總共86頁(yè)。

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

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

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