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Thus, antibodies attach to viruses or bacteria to markthem for destruction, the enzyme hexokinasebinds glucoseand ATP so as to catalyze a reaction between them, actin molecules bind to each other to assembleinto actin filaments, and so on. Indeed, all proteins stick, or bind, to othermolecules. In some cases, this binding is very tight; in others it is weak andshort-lived. But the binding always shows great speciftcity, inthe sense that eachprotein molecule can usually bind just one or a few molecules out of the manythousands of different types it encounters.
The substance that is bound by theprotein-whether it is an ion, a small molecule, or a macromolecule such asanother protein-is referred to as a ligand for that protein (from the Latin wordligare, meaning "to bind").The ability of a protein to bind selectively and with high affinity to a liganddepends on the formation of a set of weak, noncovalent bonds-hydrogenbonds, electrostatic attractions, and van der Waals attractions-plus favorablehydrophobic interactions (seePanel2-3,pp. fl0-lff). Becauseeach individualbond is weak, effective binding occurs only when many of these bonds formsimultaneously. Such binding is possible only if the surface contours of the ligand molecule fit very closely to the protein, matching it like a hand in a glove(Figure 3-36).The region of a protein that associateswith a ligand, known as the ligand'sbinding site, usually consists of a cavity in the protein surface formed by a particular arrangement of amino acids.
These amino acids can belong to differentportions of the polypeptide chain that are brought together when the proteinfolds (Figure 3-37). Separate regions of the protein surface generally providebinding sites for different ligands, allowing the protein's activity to be regulated,as we shall seelater.And other parts of the protein act as a handle to position theprotein in the cell-an example is the SH2 domain discussed previously, whichoften moves a protein containing it to particular intracellular sitesin responsetoparticular signals.Although the atoms buried in the interior of the protein have no direct contact with the ligand, they form the framework that gives the surface its contoursand its chemical and mechanical properties.
Even small changes to the aminoacids in the interior of a protein molecule can change its three-dimensionalshape enough to destroy a binding site on the surface.n o n c o v a l e nbt o n d sligandFigure3-36 The selectivebinding of aprotein to another molecule.Manyweakbondsare neededto enablea proteintobind tightlyto a secondmolecule,whichis calleda ligandfor the protein.A ligandmust thereforefit preciselyinto aprotein'sbindingsite,likea handinto aglove,so that a largenumberofnoncovalentbondsform betweentheproteinand the ligand.154Chapter3: Proteinsamino acidsidechains/\u n f o l d e dp r o t e i nf(A)roLorr.rcfoldedproteinFigure3-37 The binding site of a protein.(A)Thefoldingof thepolypeptidechaintypicallycreatesa creviceor cavityon the proteinsurface.Thiscrevicecontainsa set of aminoacidsidechainsdisoosedinsucha way that they canform noncovalentbondsonly with certainligands.(B)A close-upof an actualbindingsiteshowingthe hydrogenbondsand electrostaticinteractionsformedbetweena oroteinand itsl i g a n dI.n t h i se x a m p l ec,y c l i cA M Pi st h e b o u n dl i g a n d .TheSurfaceConformationof a ProteinDetermineslts ChemistryProteins have impressive chemical capabilities because the neighboring chemical groups on their surface often interact in ways that enhance the chemicalreactivity of amino acid side chains.
These interactions fall into two main categories.First, the interaction of neighboring parts of the polypeptide chain mayrestrict the accessof water molecules to that protein's ligand-binding sites.Thisis important because water molecules readily form hydrogen bonds that cancompete with ligands for sites on the protein surface.Proteins and their ligandsform tighter hydrogen bonds (and electrostatic interactions) if the protein canexclude water molecules from its binding sites. It might be hard to imagine amechanism that would exclude a molecule as small as water from a protein surface without affecting the access of the ligand itself.
However, because of thestrong tendency of water molecules to form water-water hydrogen bonds, watermolecules exist in a large hydrogen-bonded network (see Panel 2-2, pp.108-109). In effect, a protein can keep a ligand-binding site dry because it isenergeticallyunfavorable for individual water molecules to break away from thisnetwork, as they must do to reach into a crevice on a protein's surface.Second,the clustering of neighboring polar amino acid side chains can altertheir reactivity. If protein folding forces together a number of negatively chargedside chains against their mutual repulsion, for example, the affinity of the site fora positively charged ion is greatly increased. In addition, when amino acid sidechains interact with one another through hydrogen bonds, normally unreactiveside groups (such as the -CH2OH on the serine shor,vnin Figure 3-38) canbecome reactive, enabling them to be used to make or break selected covalentbonds.The surface of each protein molecule therefore has a unique chemical reactivity that depends not only on which amino acid side chains are exposed, but))v8(v)INOUIe ur s o r A t o q d s o q dpue6rlaprlded^lod'urEruop[rar^asl] ruolJuotsstulladzHS aqlJo uolpuryqtlM'966t'gsE-(.vEttsz'lo!8'low' reql Surforlsap dqaraql 'alIS SupuIq-ZHS eql palEAIlrPuI leql t(E,tre uI peJatle'uaqof'u'H'a6lelLl)rl'ol'l pue eurnogeruPf,aqsurEruop zHS esoq ^ sruslueSJoIIEJo uonnlo e Suunp uouPultuIa ppLuorlpeldepv) '(8) pue (v) uaeMlaq-uaraJeJdeql ol palnqlrllP sI llnsar slql 'ssacotd Iuopuer E sI uollelnru esneJega)uPpuodsalro)jo aal6epq6rqoql'surpluop uortruSooer apudedJo dlruPJ ZHS eBrPI eql peJnpord lEql ssaJordoloN a/drndare sloqto aql pue 'ttttollalate.ftuuoqn1o,ra 3uo1 aql Surrnp eBueqJ ot tse,{i\olsaq} uaaq e^eq epqdeddlod pe}elpue6r1aql lo spr)eour.rtpIal oml aq1'anlgparolo)ete pue6t;punoq aqllo-,fuoqdsoqdeqt roJ atISSuIpuIq eql tB pelecol splce ouIIuP aql'g6t-g eJnBIcuIrlxaluooruuu!qllMpale)olspt)eoutureesoqlpelBlrfuaplseulsoJdlEuIuleqJt'0plseJIJIcedsoulruEIrMoqsseaouenbas'arag'aprldedXlodpunoq slr qlrmuleuop-oqdsoqdeql spulq rIpuof,asuleloJd€olSululeluooesureluof,uralordlIlpql'suollJpJelur ulelord-utaloJd uI suollcunJ leql appolu e sI uleruopzHs eql Jo arn])nrlsaql (8)pal palolo)ZHS eqJrorJalururaloroaql pleMolaloul asoql'selrsSurpurqpup81 ot puodserJocl.leraua8 sralsnlseseqJ'(gtI-ZEI'dd'Z-Epue 'uo1ptrparolo) are;rnsurelordeqluo spr)eoururepa^rasuol,{;ueuorln;one IeuEd aas) ,{.1snou.ardpeqrJf,sap uleluop ZHS eq} roJ VGt-t aJntIC uI pe}Er}snlllse 'aceJJnsuleloJd aql uo srelsnlJ eJolu Jo euo IuJoJ ueuo suolllsod luEue^ulqllM 'u!europaLllzHsJolapoLu'euop sr slq] ual{r\\ 'raqtue(u [1lureJ euo6urq;r;-eredse,o smar^))eq pue ruo.tl(V)lsolu aqlJo aJnlcnJ]s leuolsuelulp'uleuop-eerqlZHSaqt or pa;lddepoqlaureq] Jo Iapour P oluo paddPtu ere sleqluelu l.11ueJutalord u ^oDI eql Joarerl rfueuollnloneaql6g-5 arn6r3'pe8upqcun,{1reauro 'pe8ueqcun eJE}Eqt spIf,BoulruB esoq} 'esodrnd sHf[p uIJOC'uor]3ury S.urPruopaql o] IPIJnJc ISOIUaq] eJElBq] UIeruOp ulelord P uI sellsasoql lyluapl ol SuIcEJ]d;euoqnlona pafiec poq]etu P esn eroJaJeqlUEJeM'(yZ) sralaruoueu Z'0 ulqllm ploJ ulalord uoulluor E ,rtol-loJ urpuop E ur sruole euoq{oeq eql'ohgz o} slleJrillruapr eouenbasplse outrlleeql ueqm uele 'eldurexe JoC 'JplIruISl.1qe>lreuar eJP d.1nueJuluruop etues eql'JolsesuPuoluruos B luo4JOSJaqruau aql Jo seJnlJnrls IEuolsueurlp-eaJqleqJuorlnlo^a JreqlJo aJuapr^eJEaIJ^aoqsleql seilurEJ olul sulaloJd uI sulPluop eqlgo.tueru dnor8 ol sn llrolle seJuanbesauoue8 '.{lsnona.tdpaqlJcsep aleq a^ sV'araq pellruroareureqraprtdad{;odaqllo suorlnlo^uo){ueu aql'puoq eplldade 6urzIlolp,{q'alellsqnsau,{zuaaq} q}!MpuoqlualPAo)e ullo, ol auuaseql sale^tlles!ql'56t auuasurotj uolold aql a^oulalol (l.sslH)oulp!]s!r.{aql sarnput(20|,d s y )u r e q >a p r sp o e r r y e d s eo q l ' ( Zt - 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