INTERETHNIC RELATNS SOC 128
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Q 2008 Nature Publis ing Group httpwwwnaturecomnaturechemicalbiology REVIEW 1121er chemical biology Allosteric regulation and catalysis emerge Via a COIIIIIIOII route Nina M Goodey1 8r Stephen I BenkovicZ Allosteric regulation of protein function is a mechanism by which an event in one place of a protein structure causes an effect at another site much like the behavior of a telecommunications network in which a collection of transmitters receivers and transceivers communicate with each other across long distances For example ligand binding or an amino acid mutation at an allosteric site can alter enzymatic activity or binding affinity in a distal region such as the active site or a second binding site The mechanism of this sitetosite communication is of great interest especially since allosteric effects must be considered in drug design and protein engineering In this review conformational mobility as the common route between allosteric regulation and catalysis is discussed We summarize recent experimental data and the resulting insights into allostery within proteins and we discuss the nature of future studies and the new applications that may result from increased understanding of this regulatory mechanism Allostery can be defined as the regulation of protein function structure and or exibility induced by the binding of a ligand or another protein termed an effector at a site away from the active site also referred to as the allosteric site Those effectors that increase a particular protein function for example ligand af nity or catalytic rate are named allose teric activators those that decrease the function are known as allosteric in ibitnr M quot A f quot 39 I L 39 iuu ude muta tions and covalent modifications at an allosteric site Allostery by this de nition is an intrinsic property of all proteins All protein surfaces are then potential allosteric sites subject to ligand binding or to single or multiple mutations that might introduce the property of allostery The exceptions are brous structural proteins with uniform and stable 39 er notlikelyt l 39 L 39 due to their lack of exibility Historically allostery was de ned as the regulation of a protein through a change in its quaternary structure Allostery was typically referred to as cooperativity a term associated with allostery in qua ternary proteins in which there are four binding sites and the binding of a ligand at site A impacts the af nity for the same ligand at the other sites homotropic allostery Classical examples of cooperative proteins 39 J A J J hemoglobin Rm 1 and Fig 1l Both of these proteins consist of four subunits and exhibit cooperative effects upon binding of a ligand caused by subtle changes in their qua ternary structures In the past examples of cooperativity and allostery were limited to such multimeric proteins whereas today allostery is recognized as aproperty in monomeric proteins as well The principles that define allosteric behavior in proteins are similar for monomeric 1llontclalr State Unlverslty Department of Cnemlstry and Blocnemlstry 1 Normal Avenue Montclalr New Jersey 07043 USA ZTne Pennsylvania State Unlverslty Department of Chemlstry 414 Wartlk Laboratory College Park Pennsylvanla 15802 USA Correspondence should be addressed to SJ B slb1psu edU Publlsned onllne 18July 2008 dOl lO lO38ncnemblo 98 A A 39 qmq quotchirme 39 39 x I I I the timescales of conformational changes or changes in exibility are different depending on whether a signal is being transmitted within a monomer or through subunit interfaces In this review we focus on recent experimental data and interpretae tions that suggest that a common mechanism that of conformational mobility underlies allostery and catalysis In principle allostery and catalysis result from a common property of proteins exibility which gives rise to populations of conformers that interconvert on various timescales The binding of an allosteric effector can result in the redise tribution of protein conformational ensembles and can alter the rates of their interconversion thereby modulating active site or binding site geometries Both enzymes and noncatalytic proteins can be regulated by allosteric meansz In this review we discuss examples of both and high light the strong interdependence between views of enzymatic catalysis and allosteric regulation We discuss how protein conformational states their rates of inter conversion and the existence of amino acid networks that enable com munication between distant sites are linked to catalysis and how such conformational equilibria in a protein structure may be altered as a result of an allosteric event Important issues include the mechanism by which an allosteric effect is transmitted via amino acid networks how L 39 o I t 39 39 i altered and at which these conformational redistributions take place Generally many welledesigned experiments indicate that enzymatic catalysis is closely connected to protein motion and that the rate of conforma tional change on the millisecond timescale often presents a bottleneck to the conversion of substrate to product3 5 These dynamics can lead to changes in the relative populations of protein conformations some of which have greater affinity for certain ligands or are more catalytie cally competent than others The timescales of these redistributions of protein conformations vary Though the time regimes cannot be rmly 139 39 ran e um H 39 39 flinkednete works of amino acids within the protein millisecond to microsecond to VOLUME 4 NUMBER 8 AUGUST 2008 NATURE CHEMICAL BIOLOGY REVIEW For example Cole er al formed RNase A complexes with stable it follows that altering the rates or extent of these conformational coordinate and studied these complexes via NMR dispersion experiments on the apo enzyme revealed a conformationa ity of an effector tions can ll allu allosteric effect might be limited to the rates of interchange between differentpopulatlons and maymanifest as increased flexibility or rigidity in the global or local e8 The dif culty of seeing an allostericsignalr ing mechanism in a protein structure emphas sizes the need to develop me ods to answer such questions Recent computational analyr ses have uncovered amino acid residue nets E g iuii ti iiaii i i communication Within proteins Changes imposed on these residue networks by allosteric effects can alter important protein dynamics 4 39 39 L mri liiflm f i protein function Furthermore it ls increasr inglyclear that there are proteins in which alloy teric effects on function are transmitted through the protein asaresultofchangesin dynamicsin that energetic coupling between sites must be considered Fig 2 1244 T underlie allostery How can the residues that participate in identi ed and What percent of residues in are involved in allosterl of allosteric interactions for protein engineer ing and drug design and cabal is ysisisconvincingly V he rel H E E o otion and catalysis has been eral studies and in many lesconformati l h the reengineering and design ofnew enzymes Although establishing a definitive connection between protein motion and a E E e are several informative examples in the literas turewheresuch a link has been forged and 1c release Box 1 A timeline showing evolution of allosiery as a concept ThetlmeilfleFig 1 includes some eriments and realizations of thefield and some insight into how the mentahty of the fleid has shifte 19037The Bohr effect sigmoidal binding curve of hemoglobin to 02 was observed 19107A Hill formulates the Hill equation to describe the sigmoidal binding of 02 to hemogioblh 19587Flfsthfay structure sperm whale myoglobin solved by M Perutz and sir J u i r iiui 5057Repfesslofl of gene expresslofl covalent modification of enzyme activity and feedback inhibition of enzymes are discovered79 19637J aiiosteflc sites 19657J Monodl Wyman and J P Changeux propose a theoretical model of Corie certed allosteric transitions MWC model1 9 hland e Nemethyand R Eilmer propose the sequential modeifofaiiosr terlc transitions KNF model80 in the absence of conformational change is proposed12 198057Pfoteifl folding studies lead to the concept that proteins exist in different iii iaiiu dp quot51 l M t t icovalent are included as allosteric effectors ll t l the PDZ domain proposed by R Ranganathan50 m u u i i u l v Allosteric Allosterv wtthout ettectors contolmatlorlai lnciudepHi etc hanges Dynamic allosterv s lntloduced x Feedback Allosteric regulation networks discovered introduced SCA s l t ll i Term alios1evllc Protein39eriergv Fm Xi39an KNF model structure 39 quot Bohl etteclL Figure 1 in proteins 7 NMR rel Xatlon 1 NATURE CHEMICAL BIOLOGV VOLUME 4 NUMBER 8 AUCUSTZOOB mum u i REVIEW FigureZ leferehtmodes ofallosterlc behavior a Q Ler mahrChahgeuX MWC model of St in one 0 m5 Allostevlc etteclol Lei d Alloslellc t t eclol l A F conformations Eac su hltha a lhgslte for an allosterlc effector aswell as an active site ovel orblhdlhgslte b monomeric allosterlcally Arrog em binding lhhlbltedprotlh h blhdlhg ah Hoterlc b Alloslevlc We cw Site lhhlbltoralterstheactiveslteor l l inhlbl OV alive site I Allostellcr Site 7 Al lostev lC activatov e I Alloslevlc tteclol A F I l Alloslellc site because the activity of the enzyme ls indirectly uhderallosterlc control via the bound protein With an allosterlc 1 es site Such cohstructsare both present in nature and the target of protein engineering Stu l to the raterlimiting product release step in RNaseA and show that the u 39 39 39 These local 39 39 a F t39 39 39 39 quot large number of conformations that may differ from each other only L L PM U H I n m e 1 39 39 39 39 4 stability in a given protein For a catalytic cycle there are multiple NMRrelaxation 439 39 39 k on i A and 39 39 39 Mnrm r th 39 t i i i i I ti n 39 47 be functionally importantZW I 4 r n app c is or r it k s l c I L dihydrofolate reductase DHFR from Excherichia 0113 Similar N39MR The interconverting conformations have similar energies and the L39 39 39 L 4 39L 4 L native state 39 39 quot 39 E can lead to a d1ange in the distribution of protein 39 molecules that reside in the same or different conformational states 39 39 l Fig4b 33 39 l U l orN39MR 39 b nbrl t39 p t the average t m m L c c n E s a 1 ml 2 nt 39 l 39 quot tln n milati n 139 l t r i m a m highlights the role that such changes play in 39 These Changes in distributions of protein conformations site The idea that there is a network ofphysically interconnected and I m 39 m librium between H 439 I 39 M v v of may 39 vet anoealin 4 L studies that M WM m s c c 139 39 39 m 39 transfer in such a network has been discussed in the literature An A is i no c u c ensembles of conformers and that proteins unfold VOLUMEA NUMBERB AUCUSTZOOB BIOLOGV 1 partrcrpate rn ary conservatron of these communrcatron networks The sensrtrvrty of rrrprra r rrr rnterdependence between the network resldues The changes rn protern structure that result from brndrng of an allose terrc effector are by de rnrtron rntrmately lrnked to protern motlon But how does the blndlng ofan alloaterlc effector atone slte ln uence the propertres at another slte How do the two srtes often removed by a great drstance even 20730 A communrcateAn amrno acrd that rs can ln some cases have a profound rmpact on catalysrs or brndrng Th 1 1 tron or mutatron can be felt through great dlstances Does the effect transmrt vra subsequent rnteractrons between resrdues lrke domrnos followrng a channel rn a proteln Answers to these ques r ns can rn some cases be rllumrnated besray crystallography from comparrson ofstatrc structures rn therr free and boundst tes Z Addltlonal blnds lng and thermodynamrc studres vla rsothermal tltratlon calorrmetry lTC elect on fl 1 L steadystate and trme resolved have been the marnstay ofstudres of allosterrc proterns An experrmental approach to rmplrcate the rnteractron between two rements of a double or REVIEW r 1 rrarrrr r rrr l rk h alternatrve approach developed by Rama Ranganathan and colleagues uses a sequencesbased statrstrcal analysrs SCA method for estrmatrng 5 The prrnclple behrnd thrs approach rs that rf two srtes ammo aclds rn a protern are theys oul L should be evrdent from astatrstrcal comparrson ofhomologous protern sequences The coevolutron could result from erther structural or funcs tlonal factors ln both cases mutatlon atone resldue would statlstlcally la l V In 0th r rd srdues Thls analysrs requrres the avarlabrlrty of many homologous on n r r r rr are coupled for structural or functronal reasonsAsshown by Chl ernl couplrng between resrdues however lt can sometrmes be explalned by a ul rarr ra usrng functional structural and foldrng analyses can give lnsrghts rnto res mr ht parse the network of coupled resrdues rnto those that have coevolved prrncrpally for functlon Usrng SCA Ranganathan and colleagues rdentrfred a network of coevolvrng resrdues that structurally connects two drstant but functronallycoupl d46 or Prperer 3 A E Hydrlde v n1 rm dadouble mutant analysrs on the r trahster 39 j Voltagessenslngmoduleofthe ERGlchannel l Max 39 39 rc r atransm mbranec annelspecrfrcfo r 950 s r f K thatsensesvoltagechangeslnthecelltmemr E NADPH DHF brane potentra They rnvestrgated the potenr model E NADP39 tolate E NADP39 THF enlng andrnactrvatron closlng ofthe channel are functronallycoupled tomovement of the ole ellx 4 on d negatrvely charged resrdues result rn the der ferent voltage dependencres of actrvatron and lnactrvatlon that have been observed Arg531 was energetrcallycoupled to aspartate resrdues 411455 and509durrngactrva nbut coupled only to resrdues 455450 an 09 near the extracellular portron of 2 and 3 durrng Frgurez rnactrvatron r 5 r460466 change rnvolvrng resrdues rn many parts ofthe Cotactor 200 8quot release 260 Squot ETHF A E NADPH THF togetherwrth The rar r lllnlll rr r t M a and rrr rru lul ofeaoh lntermedlate tn the catalyth cycle As represented by the oolorsoherhe tn the gure for each voltagesensrngmo u Memed ates A drawback of double or multrple mutant cycle analyses rs that due to therr labors mrnr n m and the black arrows show the oohforrhatrohal lnterconverslon rates obtalned from NMR relaxathrl 3 c c frorhth t f orthe NATURE CHEMICAL BIOLOGV VOLUME 4 NUMBER 8 AUCUSTZOOB REVIEW Reaction coovdlnate FlgureA for ai ii u iii a in contrast iai iiuii leadingl a in i This figure illustrates multiple populations of conformations intermediates and transition states For actual enzymes the number of maxima and mlnlma wn along the coordinates is expected to be greater than she a c c from ref 22 b lland ill for on the protein energy landscape The black lines represent the landscape in the absence of an allosterlc effector and the red lines representthe effectorr boundstate i eii ii leadingto a conformation With a malarity population ii Effector binding leads iii onformation eii ii ll llll l 8With permission from Elsevier functionally connected sites in FecA a membrane transporter protein that actively pumps ferric citrate into Gramrnegative cells and as a activation FecA TonBr dependent receptorswhich are signalrtransmlttmg irbarrel proteins k esting to note that the network that emerged from the SCA analysis is 39lquot D A binding sites Fig 5 A analyses of on in ui i between the periplasmic TonB protein and 3 latecl53The binding ofTonB to the Nrterminalsequence ofFecAcalled the Work to con rm the involvement of these residues in the mechanism A ric citrate FecA consists ofa 227stranclecl irbarreli an internal plug that M th TonB box The results from theSCA analysis on the FecA transporter highlight linked conformational changes cannot be seen in crystal structures ligandel i i39mrl E triggers several local conformational changes in the extracellular and apical loops ofthe barrel and the periplasmic pocket of the TonB box 39lquot D H lw L in other words both enthalpic and entropic factors have a role H As a iiiiiiai Fu Popovych ernz used NMP relaxation measure across the protein family As so often is the case inspection of crystal the regions of conformational change it is possible that the propar gated conformational changes are sosmall that theycannot be seen in all Mr 3 i ii munication between the iron L A L FecA the Panganathan and colleagues addressed this question by performr ing an SCA analysis on multiple sequence alignments of a large group of39quot u m t t min ti nofPU lTCexperime demonstrate that allostery can take place in the absence of detectable conformational changes and be exclusively mediated by transmitted changes in pr in motions in the dimeric catabolite activ CAP5 The binding ofa single molecule of cAMP to CAP lowers its affinity for a second molecule of CAMP but has no effect on the cone formation of the second subunit The dynamics on the other hand m to nanosecond timescale Fig 6 Moreover the flexibility of CAP as measu ed L quot P ht nvirin lin i i Munu u mono begin arm ll inf g mnnln adjacent L bindin site and end in the periplasmic pocket near the TonB box physically e bindin it Fi uenchecl q aiiii ipiiibiii linkingt iti int y in the absence of a visible connectivity pathway VOLUME4 NUMBERS AUCUSTZOOB BIOLOGV This is a result similar to that of FecA In the case of FecA the binding effect was assumed to propagate throu h van er between residues in the physically connected networkThe results seen for CAP are analogous in the sense that changes in fluctuations take place in regions linked by cooperative interactionsThis study among tln v conformational ensembles and protein motions ompu a ional studies present a complementary method to NMR for studying the llnk between the chan longerange propagation of allosteric Slgnalssg This was illustrated by Zhuravleva ernl in their study of the chan emi shift n dynamics of the RNase barnase u on binding to its natural inhibitor barstar Xeray and NMR structures showed that the free and bound a quot3 a Q E E g 3 REVIEW As a test case for this method the authors studied the von Hlppela p i m p mutated in von HlppelrLlnclau cancer predisposition syndrome char acterized by the appearance of tumors in the central nervous system lzirln 7 tin is one of these proteln pVHLwhich has two domains of and 3 is a aadomaln to elongin c The pedomain of pVHL interactswith hypoxr larl ducible factor HIPwhlch is regulated by the pV39HLrelongln 0 complex Fig 7 The mutation Y98N is one ofthe carcinog nic muta tions in pVHL It leads to further loss of pVHL stability and comes d pi ln in urn r r in and Molecular esheet that is located far from the binding interface upon binding of barstar e a r rd ntin dbysimulationsTheseresidueswere fashion l l and W N lzed the observed changes in NMR parameters upon ligation in terms N o han in A t brim states 39quotL L A 39N39MD A l fun ti n binding in yon U W l l A 4 across a protein L A Allostery in drug discovery and protein design could perhaps be used to investigate the potential binding of inhibie ors at sites by introducing a cysteine residue quot quot li rm oft l 17 be l li ands Ligands that bind in the vicinity se ective across species because while the active sites may be relae tively conserved the evolutionary pressure on allosteric sites has been 152 itors have been extensively investigated for G protelnrcoupled receptors kinases and llganclrgatecl ion channels H Extending allosteric inhibition to other he been identified by high t ughput s n i hem hanism ofinhibitionforatarg m by klnetl allostery is implicated the bindingsite for such i i of these critical positions would possibly be covalently linked to the enzyme by a disulfide bond and could be detected by mass spectromr etry This approach has been reviewed by Erlanson ernz 69 Fragments HA The chelated a compound should be further experimentally determined by methods such as Xeray crystals lographyNMR fluorescence studies or crossr linking experiments Nussinov and Liu have Hg 5 T D Proposed a general strategy for Identi cation blue spheres H in ribbon diagrarns three differentToriBadepehdehttransportersiFecA a Fh mm o o Ni m examination of covariance matrix maps a ferrlchrorhe for b and vitamin 812 for c that are pumped into the The network l dl Comparison of covariance matrix maps for a ligand boundtoan unbound proteln can reveal which reslduerresldue correlated motions change upon ligand binding and hence can suggest new allosteric sites ohelated TohB 48 SEA network residues E110 E56 and G32 in FecA FhuA and BtuB respectively are deerned responsible fora speoifio polar interaction with TohB in BtuB are located in the re SCA network residuesVll and T10 in FhuA and v9 and V10 spectlve TohB boxes that likely physically link the ooeyolying network of the barrel and plug to the signaling dornain NATURE CHEMICAL BIOLOGV VOLUME 4 NUMBER 8 AUCUSTZOOB 1 la I WWW l eq CAMP i l eq CAMP DActlvated gt gt Kn o 04 ulu Kn 4 W AporOAP CAMP VOAP CAMPQVOAP ure 6 Summary of l O r arld the blue spheres lhdlcate suppressed rhotlohs lh the apo state lh Oh p O thehl la lhlhOh O ll Atlrhe domaln as lhdlcated by Blrldlrlg of the mlcror to O urn til 54 that act as alloaterlc effector to stablllze the 113 Interface of pVHL could be lncorporated lnto compound deslgn However fragmentr based drug desrgn llke multlple proteln mutagenesrs to alter proteln speci city presupposes the addltlylty of lndlyldual effects Gwen the u l upun uh tO In other t m dlrec tlon for ratronalsynthetrc efforts ln medlclnal chemrstry For example r A Jr a a n l r It ls ofgreat lnterest to deslgn ultrasensltlve swrtches that can be bullt from lll uula h ha r v ular functlon to sense cellular condltlons and to perform functlons pathway ln response to the lal taut ATP blndlng slte7 gt7 A p at a u l h nan new allosterlc lnhlbltlon sltes lnto the proteln tyroslne phosphatase FTP r r n our r lated bya cellrpermeable fluorescern arsenrcal halrpln blnder FlAsH a lnserted ln the catalytlc domaln of PT at yarlous loop posltlons A on of the resultrng mutants expressed as soluble enzymes of FlAsH slmllar to those ofthewlldrtype PTP Conversely when lncubated wlth FlAsHthe catar E r reduced In one PTP yarlant m whlch the lnsertlon posltlon was 17 A removed from the catalyth cysterne FlAerlnduced lnhlbltlon was 127fold In another mutant ln whlch the replacement was located more than 20 A from the catalytlc cystelne the lnhlbltlon was threerfold From rnspectron oftheeraystru 6 0 es now e ge a ou e mec anrsm ofallostery can be used to desrgn useful proterns that exhlblt swltchrllke behavlor73 75 A new swrtch can be created bycovalentlyconnectlng an enzyme to a llgand blndlng domaln that blnds a small molecule In these swrtches the mechanrsm of functron between the enzyme the output domaln and the llgand blndlng domaln lnput domaln rs complex and cannot necessarrly be predlcted Fig 2e Swltchlng mlght depend on a conformatlonal or e r d m ln Guntas eral constructed allosterlc swrtches that responded to maltose blndlng by comblnlng E col maltose blndlng proteln the lnput domaln to TEMl 539 L p A m r llulal llolll ll wlth of longrrange communlcatlon ln proteln structures As new methods drspersron NMR methods and Xeray crystallogr relth e to understand the stunnrng catalytlc power of enzymes the freld of n r r r n n n Allostery and O l t r ft r all Flg re 7 The crystal structure of a tumor suppre u ssorprotelh complex The structure of the HlFrpVH L red and cyahpe ohglh c greehrelohglh B purple lSS own Tyr98 are noted lh purple from ref 68 VOLUME4 NUMBERS AUCUSTZOOB BIOLOGV Q 2008 Nature Publishing Group httpwwwnaturecomnaturechemicalbiology intimately linked since allosteric effects impact one or more of the fea tures of catalysis ligand binding ligand release and the chemical steps in between Whether allostery is always transmitted by channels such as those identi ed by SCA and how involved a subset of amino acids is in a protein are both challenging issues Identification and prediction of amino acid networks that support allosteric effects is an important challenge and SCA and other met ods will ikely be the basis for the next signi cant advances The timescales of the dynamics implicated in allostery and in catalysis need to be subjects of expanded investiga tions to determine differences and similarities as well For example in the work described above on cAMP binding to CAP only the motions on the micro to millisecond timescale become suppressed as the rst cAMP is bound but upon binding of the second molecule of CAMP both the micro to millisecond and the picoe to nanosecond motions are suppressed We expect that both the micro to millisecond and the picoe to nanosecond motions will be found essential for allostericity within proteins As discussed inthis review we have learned much about the basis for and pathways of allostery but much work remains to be done to fully understand and harness these principles As more allosteric sites are 391 quot39 J mdied and the 39 39 39 between an allosteric site and a remote site are elucidated we anticipate that it should become increasingly feasible to computationally predict new allosteric sites in proteins The advances in understanding allostery are also being used 39 39 39 39 39 J 39 39 an input domain is connected to an output domain These switches may prove n efnl 39 39 1 tate an 139 39 r ccutiu funce tions such as drug delivery in response to that state Understanding the 39 39 f 39 39 L 39 ill allow the building of increasingly complex and sensitive systems for multiple uses 1 1 WJlLLlC LU wuiui ACKNOWLED GMENTS We ank S Hmmeerchiffer for helpful discussions Published online at http www nature comnaturechemicalbiology Reprints and permissions information is available online at httpnpg nature com reprintsandpermissions 1 MonodJ WymanJ amp ChangeuxJ P On the nature of allosteric transitions a plaur sible model J Moi Bioi 12 887118 1965 2 Kuriyan J amp Eisenberg D The origin of protein interactions and allostery in colocalizar tion Nature450 9837990 2007 3 hr D D McElheny D Dyson H J amp Wright PE The dynamic energy landscape of dihydrofolate reductase catalysis Science313 163871642 2006 A Luna P Berlow R B amp Wat E D Characterization of enzyme motions by solution NMR relaxation dispersion Acc Chem Res 41 2147221 2008 5 Watt E D Shimada H Kovrigin E L amp Loria J P The mechanism of raterlimite ing motions in enzyme function Proc Nati Acad Sci USA 104 11981711986 2007 6 HenzlerrWildman K amp Kern D Dynamic personalities of proteins Nature450 9647 972 2007 7 HenzlerrWildman K A etai A hierarchy of timescales in protein dynamics is linked enzyme catalysis Nature450 9137916 2007 8 SwainJ F amp Gierasch LM The changing landscape of protein allostery Curr Opin Struct Bioi 16 10271082005 9 Agarwal PK Billeter S R Raiagopalan PTR Benkovic SJ amp Hammeerchiffer S Network of coupled promoting motions in enzyme catalysis Proc Nati Acad Sci USA 99 279472799 2002 10 Bode C etai Network analysis of protein dynamics FEBS Lett 581 277672782 2007 11 Suel G M Lockless SW Wall M A amp Ranganathan P Evolutionarily conserved networks of residues mediate allosteric communication in proteins Nat Struct Bioi 10 59769 2003 12 Cooper A amp Dryden D TE Allostery Withoutconformational change A plausible model Eur Biophys J 11 1037109 1984 13 Gunasek ran K Ma B amp Nussinov R lsallosteryan intrinsic propertyofall dynamic proteins7 Proteins 57 4334143 2004 14 Kern D ampZuiderweg E R P The role of dynamics in allosteric regulation Curr Opin Struct Bioi 13 7487757 2003 15 Bus Catalysis and binding of cyclophilin A With different HlVrl co DA amp Kern D capsid constructs Biochemistry43 611076119 2004 16 N U 4 Nature 450 8387844 2007 26 28 29 U is U Ln 39 is o 41 is N 44 is Ln 45 is l REVIEW Bosco D A Eisenmesser E Z Pochapsky S Sundquist Wl amp Kern D Catalysis of cistrans isomerization in native HlVrl capsid by human cyclophilin A Proc Nati 39 99 524775252 2002 Cole Loria JP Evidence for flexibility in the function of ribonuclease A Biochemistry41 607276081 2002 LouisJ M lshima R Torchia D A ampWeber l T HlVrl protease structure dynamics and inhibition Adv Pharmacoi 55 2617298 2007 Katoh E etai Asolution NMR study of the binding kinetics and the internal dynamics of an HlVrl proteasersubstrate complex Protein Sci 12 137671385 2003 eedberg D etai Rapid structural fluctuations of the free HlV protease flaps in solution relationship to crystal structures and comparison With predictions of dynamics c a Massi FWang C amp Palmer A G lll Solution NMR and computersimulation studies of active site loop motion in triosephosphate isomerase Biochemistry45 107877 2005 Benkovic SJ mes G G amp Hammeerchiffer S Freerenergy landscape of enzyme catalysis Biochemistry47 331773321 2008 Osborne MJ SchnellJ Benkovic SJ Dyson HJ ampWri ht PE Backbone dyname ics in dihydrofolate reductase complexes role of loopflexibility in the catalytic mechar nism Biochemistry40 984679859 2001 KA etai l quot traiectory Brath U e M Yang D Kay L E amp Mulder FA Functional dynamics of human FKBP12 revealed by methyl 13C rotatingframe relaxation dispersion NMR spectrosr copy J Am Chem Soc 128 571875727 2006 Mulder FA Hon B Mittermaier A Dahlquist FW amp Kay L E Slowmternal dyname 05 hr t in nnli ii quotM u in a cavity mutant of T4 lysozyme J Am Chem Soc 124 144371451 2002 Cho W etai Distribution of molecular size Within an unfolded state ensemble using smallrangle eray scattering and pulse field gradient NMR techniques J Moi Bioi 31610171122002 Hilser VJ amp Thompson E B lntrinsic disorder as a mechanism to optimize allosteric coupling in proteins Proc Nati Acad Sci USA 104 83118315 2007 Luque l Leavitt S A amp Freire E The linkage between proteinfoldingandfunctional cooperativity two sides of the same coin7 Annu Rev Biophys Biomoi Struct 31 2357255 2002 Daily M D amp Gray JJ Local motions in a benchmark of allosteric proteins Proteins 67 3857399 2007 Weber G Ligand binding and internal equilibria in proteins Biochemistry 11 8647 878 1972 Freire E Can allosteric regulation be predicted from structure7 Proc Nati Acad Sci aharl Coupling between global dynamics and signal transduction pathways a mechanism of allostery for chaperonin GroEL Moi Biosyst 4 2877292 2008 Amaro R E Sethi A Myers R S Davisson VJ amp LutheyrSchulten Z A A network of cons Biochemistry46 215672173 2007 Masterso L R scioni A Traaseth N J Taylor S S ampVeglia G Allosteric coopr erativity in protein kinase A Proc NatAcad Sci USA 10 5067511 2008 Rakauskaite R amp DinmanJ D rRNA mutants in theyeast peptidyltransferase center reveal allosteric information networks and mechanisms of drug resistance Nucieic ndeszuentes N Fiser A amp Casadevall A Exchanging murine and constant chains affects the kinetics and thermodynamics of antigen binding and chimeric antibody autoreactivity PLoS ONEZ E1310 2007 hyaya TJ amp Gray J J Contact rearrangements form coupled networks from local motions in allosteric