•
`CIE
`
`15 NOVBMilllR 1991
`VoL. ;i,54 • PAGES 909-1080
`
`$6.oo
`
`r\1!ERICAN
`AssOCIATION FOR THE
`ADvANCBMllNT OF
`SC!ENC!l
`
`NOV 19 \9~\
`unN&rally ~t ~1:1. ~•rn .~.:c\···
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`"""di~.: :'
`
`90l'iS"
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`£0llJ K*
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`IH
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`lS NOlAV01
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`HISNOJSIH .
`9!1 AHd039 >.001~
`9fi'[6tlZ6/£0/IO SV9'i{?g0600000
`t._J°
`lllOS llJ-UVJ l(-!OOOl-lC-M-lll-4ll!KlOll0011110Uf
`
`Breckenridge Exhibit 1017
`Breckenridge v. Novartis AG
`
`

`
`AM.EIUCA..i""J
`ASSOCIATION FOR TliE
`t\1>vANcP.-.\!E~r 011
`S(:IENCE
`
`MQijijilk§li§b
`
`llli§d.tQt
`
`•
`CIE
`
`CE ISSN 0036-8075
`
`15 NoVEMllER 1991
`\'OLUME 254
`NUMBER 50,\4
`
`915
`
`'ll1i~ \\'eel; in Srk1u1'
`
`-·---------~----------
`
`917
`
`918
`
`'Ilic J...iml ofd1c DJmmed
`------------------------~- -----
`$,inuitk ~li....:on.hKt lnv.:stlg,uinih: \\'ho Should Condon 'll1tm?. D. F. K11.1s •
`l'hy!ot:cn~· .i.nd Dh· ... ·rsif)': C. Klt--\ft-.\'.'~t~I • E\1in<.1ion "Hot SpnH": N. l-.11'1.I\\ • T<ni<·
`\\';nt( Ck.uiup: D. \V. \Vou· A~CJ L E. Gl\H·I'. u PCBs in the F.nviiomn(m:
`JI. ll<HFf'rI,\ AN[) H. VAINH>; <i. \\'. i..Jl\111111 ~-
`
`llriglit(r pro~pc.:ts fin ~olJr ld\'S\.'.op1.·; p!.111ning .ui t\nt,lr\.'.tk CVJ\.'"l\.11im1; n ... '.
`~~~~:;~-;~g of the ~1inds on ~he5tos.• C<)HS~lhU\ Report Duws Fire J~~;~~\~-;;;1
`E:1.1n:mcs • "-ll1ird \VJV\'": Roiling the \V,ni:rs
`S..:itntilfr S!nnh~ Soln:: ·' ,\\urda ,\lp1t·11·
`JIU(IO TJke~ on Role as ~hniJ~I'.' llr1•k(f
`I lughc\ lnV(\tigJtor> Rile NH I l\:,·r R<·vicwers
`Hli~f/11-.:1; Q11cs1io1H Raised <Jfl ,\!Jth Rankings• RJling Unh·cnif}' ll&D (cont.)•
`CJ.td1ing Soml'.' (Co\mi.:) Rays • !'itu,knb ·111wJrl USDA P~t P!Jn • 1\n kc (J.p 011 thl'.'
`1 lott(H l'll11ct~ • l'rimarologi\1 lhnJ Together 111 Rd.iring Seil'.'n<I'.' 10 tht• l' ... ·opk
`
`931
`932
`933
`9.l4
`
`936
`938
`939
`941
`942
`
`944
`946
`
`953
`
`954
`
`!low l.ong h the llunun Li!(.·.span1
`·nit· Sound or Ont: Dune Rooming
`Puning Einstein 10 1hc TcH~in SpJCI.'
`1\IDS: 111c Evolution of an lufcCtion
`Ex1inftio11 Potpourri: Killers and Victiin~: \Vhcn:: to Run From a Ii.la..~~ lhtinllion1 • I'l.1ti:
`Tt·ftonks J\ a Dri\'cr of Evolution • Looks Ll~c th\.'" YtKJlan I luh.h a Killer Cr.Her
`
`\\'hat N<:xt in du: Galin CJ..~d
`John Cr..-wthon: Sden.:e Jounulht J\ lin-.·>tigJ11)1 • Repart C~ul on Crcw.!1,on's Rcpott111¥,
`
`----------~-----
`
`Rt'(o:ptor·lndu,cd Conformation Clun'~(' of lhe lnunuuH•upprc~unt C)'dn1.porin i\;
`K. \V0-111k1c11, n. voN FH.EHll'l\l>, c. \V1;1n'.I\, <..J. \V1uF.R, R. TM1n.R, It. \Vu1,\wR,
`\\'. HR,\UN
`Rw1ting of the Lxk and Key ~kxkl fo-r l'rl'>td1t·l.ig.u11I Hi1kling: \\'. L. JoRGEJ,.\l'N
`
`Chlll~('\ in the \\'nt Ant.l.fflk kl· .Sh('d: ll. II. 1\1.l Er ANH I. ,\L \V111u ANS
`959
`963 Amigrni' Di\'a-sity llncshok!s .ind 1hc Dl"vdt)pnwm of AIDS: ,\1. A. NoW,\t.:,
`lt. ~i. ANDI'.RSON, A. R. /\1cl.EAN, T. F. \V. \\'ou·s, J. Goun.S.\llT, ll. ,\t. ,\IAY
`
`970
`
`974
`
`981
`
`9R.'
`
`•
`
`•
`
`Ek\.'.tronk C.Airrcbtion Effrns Jilli Sup(:ffotid1Ktivity in DoJXd Fu\lcrcnc\:
`S. Cll.\t.:l\A\'Alln·, l--1. I'. Ct-tJ'ANn, S. Kn·11.~0N
`l'ro!tin I lydrJtion in Aqucou~ Sol1Hinn: ll. ()n 1:-:u, E. l.Jf.l'INSH, K. \V0111R1c11
`
`X·rJ.)' DJnuge lo CF3CC)i-Tennin.ti"'i OigJni.: ~10001.\yers on Si/Au: PtirKipll E!fo1.·1 of
`Fk ... ,n•n~: I'. E. L-\EHINI<;, R. J.. <.::tAH \.\\, 11. A. llu mirct-::, <.;. ~t \Vunl'.~JnJ'.\
`S\.'.11111in1~ Tu1111ding ,\1icro,..:opy c1ft;Jk11.1 (100) S11rfa..-..- Oxid~tion lnd Sorptinn of
`1\•1uco11~ Gt>ld: C. ~I. Ec;c1.t~sro:-i ANP ~I. F. llocnH.t.A, }11...
`
`SC!CtiCE (ISSN 0036007!>} It pubU1h!>d wHUy on r1ld1~, fXttpt th• la1t Wt4k In Otc.err.b.11, by tho Am•1IC.1n
`At~l,\lon for thl Advill(em•nl ol Stltn<(', 1 :l.J.) It St1ut. tUI, Wa1h!ogton, OC 2000S. S<.'i:.c.-,j dass rv~ti!-;<i
`(po .. {>\.i,>1'.i-:;w1 tki. 4C.He-0) pa\d al Wa~hh,~,;.-1, oc. IU><l ll-OJ.~;.;."'-11 IT'3.·!·~ c;'f.:;:.:'$. C<.>;r,T>:I• '"' 1.,.)1 "tr/ !hi! Arr....O-;.a11
`MW;i.\~i,.-.1 k.r ttw M.·;u-«e<r.<¥.t c4 &i.in....-, Thll tM SCll:.NCE i$ a f"V'rtHed tr;;.~. ol ti"~ M/<S. ll«m.51<:
`.-.&,.;.jLc\I mt'rr.bc!fshµ ii.rd sul:iso-i:'kvl (51 !~~s): $<;2 (~·H a»ocatN lo subsc.-ipt.00), (X..T&-H<:- ~·41.t..'(J<UI
`hl~t~ (St iswc-s): SIM. f(.tc?, ~""'S"l "~t.a· )..!~....<;..). C&U.-..">..31l ('l>Jfoc.ama?) !50, frhor o.: .... !ri.·-~ (,\1 .u.~lsl
`dt.\.·,ffr) $!15. flrdd..1.S.!, ~ sa>:k.-J vo:l '-"T~lt~ r~fe!i OOH~. C.a'\i'ld.Yl JiY'-"'>V.'ChGST ,..,.,'!J • .,tJq lJJX"'
`rcqu..'St. OST '12$-1 S.9122. Clung• of ~ddrtu: ~ G W\.""~-S. 9'ffi.l ('.l1d anj tv:'lf a.X!r(-S<,.(<$ ....... J 11 6.g'f a.:-i:>:-.... 1
`~. Po1!.rNliter. S«d dlar._;<i of ad<:kllios tn Sd..'n-.,. P.O l'-0~ roJJ, JJ.ar~. OH .f;\))5.. "'..-.:.3 Slngl• copy
`Wt•· Ml oo ix-r IM>.»~ w.iom wt-aw ~~1.!tQ"; G~ 1<> ~-..:~ P1oo..>.-ts '-"-» t~-~n.r•r-"<ts, $2\l. Our..:
`tu\<!s oo t&.'.jt.JY..t /l.u\horuA;Uon to pholocopy n1:.~~'fi.V ki lrt(1n..'4 « ~$1.Yl.:-tl UStl 1.11-... -<.,;r ci"Cl.~ r.:>1 l<>''tr>J
`v.itlkl tM IN/ u~ pt(ulsiMs or tt~ Cqrjlighl Ad 1$ l)IN.t.xl b'1 AMS lo l.«arics arid Clile-f uws 1t'\)'.:;.lt1eJ v.r.h ti-.,
`C-op,Tef4 CINWMCOC<°'ft.E'f (CCC) Tr.lns..1'f.>oo..\J R~~fr>J Sc<.',.;(I, prer.-ldod lh:.t th;'! b.'\S<)f~"' $1 p...~ c..w pi...;
`S-0.10 p<-.i P.,l<)(l is pa;d ~ft0..'1.'f 10 CCC, 27 Corlo}e$i $tr~~' :h.l._"'lln, M.u.!.rliose:is 01&70. TOO ld&M.:.v>c.1 t>:M lot
`SO\V>.-.,1$ 0036-007~1$3 SI t .10. $dtH!Ci'ls h~..-eJ in tho lloJJJ..v's Gtf.:1.9 to Pai:J.;aJL~>rolhlr'1tl.n.l In sv.w.il
`$pc.O.t~l(.ct ln:\('ll),$
`Ttw An .. "o.·ar1 kNxil!«l fl:,.. 1h9 Mr.Jif:i.ifr"'.f!~ nf &W<-.:.-i was k....-..Jod in 16-113 am in::<:.<"r.ora'.ed in 1674. t:s ot.;......_'i.,..:.--s
`il'<l t) h~\h<)f ttl<l v..:O. ol V~ftl\~1s, I·) fu>1•,,.~;i "Nl"''"'.ic<1 <'.IT•:.•3 l~..:.'m. lo~ srief"Mic ht'-f~::<n ar.J 1e1.pon;;t>litf. lo
`im;'.tv.u lh.1 <-r ... -.::tt.w.;s<; c4 scie<>o:>:! II) 1t.3 pr<~u.:lX•l (I. l1uman v.i!!"Jte, lo c;dvar~ C·ducatai ~1 50-c..-.:o. ar.J lo
`..-.:iN~O ,._,i;i.c ur-0..>r,,.\;i.r,jo-q and lt;'.J\:(C-c'.-;:,::..1 d the iH(U1.. .. ·.::>J .vd r'e>mG c~ u-.., rr.;;-th:.Js. o4 ~.;.__v.;-;i ;,, t>1.1'T\.;.1
`
`~>'(>J>"(•"i.\
`
`

`
`l 0 i'> located on the oppo"ite side of the ring plane. For the [X>lypcptidc
`b,Kklx111C the stn1ctural rc.Jn;1ngcn1eot upon binding to the receptor is
`rtrninisccnt of rhe in\'Crsion of a glovi.:, \Vhcrcbr the hydrophobic
`exterior edges fonncd by the N-1nethyl groups in fo:e C'>A .ue rcpfaccd
`by a polar surface of a1nidc protons and carbonyl oxygens.
`"flte confonnation of the receptor-bound CsA indicates the
`po-~sibility of hydrogen bonding \Vith the rcci::ptor protein. For the
`aniide proton of Abu 2 the presence of hydrogen bonding is directly
`supported b}' the observation of .<:,lo\ved cxdungc with the soh•ent
`(10). Hydrogen bonding is also con1patiblc \'lith 11--1- 11·1 nuck-ar
`OvcrhatL~er efii:cts (NC)Es) observed bct\vccn CYP and thi: residt1l'-"
`I to 3 and 9 to 11 of CsA ( 10> 11 ). 'll1c dr.unatic global rc;1rrangcn1ent
`of the polypeptide backbone conforn1ation in CsA, \Vhich enables
`recognition b)' hydrogen bonding, is particularly rcn1:.ukablc for a
`cyclic co1npound, \Vhich has a great!)' reduced accessible confor-
`1natiun space when compared with a corresponding line.tr poly(cid:173)
`peptide. Considcrint~ the in1portant role ofrnolecul;tr 1nodcling in
`dn1g design, it is instn1crivc to note that 1nokcular dyna1nks
`calculations that started fron1 the crystJI stn11.:turc oc rhe solution
`strucrure of free Cs A and ch.a used diHCrent potcntbl li.1nctions to
`re pre.sent the solvent ( 15) gave no indk;ition of JU in1nlincnt
`n1ajor conforn1acion change away fro111 the starting conformation.
`Thus C..sA may \Veil end up as a textbook case to illustr.Hc the
`i1nport;ince of experitncnul 5tudies \Vith both free and ren:ptor·
`hound cfkctor 1nokcuks fOr untkrst;tnding s1n1nure-f\lnction
`corrdauons a~ .l guide to i1nprovt·d rno[ecular design.
`·r11e NMR inve~tigation~ of receptor-hound CsJ\ were pcrt(>rnicd
`with con1bincd use of i~otopc-1.lhding and hetcronudc.ir Nt>.-tR
`cxpcrin1cnts. In •111 unlahded systcn1 the largl' nun1lx·r of protons
`fro1n the receptor protein would interfere \\'ith the ol\SCrY•Hion of
`the resonance lines of the ligand. l-Iowc\·cr, binary con1pkxcs arc
`ide,\ll)' suited for studies \Vith ellicic1u labeling sd1cn1cs, because the
`f\\'O co1nponents can be labeled sep;u;udy \Vith 13C or lf;N before
`con1plcx forn1ation and subst·qucntly co1nbined \vith unlabeled
`partner n1olecules. Suitably chosen hcteronudear editing schen1es
`(16, 17) can then be used to separate the 1H N1\lll lines of the t\VO
`n1olccules in the con1plcx. In particubc, US(' of the so-caHed heter·
`onudear half-li!ters (17, 18) in 21) 11-l Nt\lR spectra represents a
`valid alternative to the use of three or higher di1ncnsional cxrx:ri·
`1ncnts for irnproved resolution in such systcnis. An intrinsic advan·
`
`rnge i~ that the 21) 1H- 11-[ Ni\1R spectra c.1n be recorded \Vith
`sensitivity and digital resolution (01nparablc to thme of correspond·
`ing conventional 21) 11--I NMR spectra. \Vith 1 ·~C-labded C.<;A a
`doublc-h.tlf-filter technique w.ts panic-ubrl)' hdpful (19) lx:causc it
`produced diflCrcnt subspectrJ th.H contained eith~·r exclusively in(cid:173)
`tr.1111okcular NOE cross peak.'> hct\\'l'Cll diflCrcnt protons of(:<;A or
`diffi:rcnt proton'> of CYP or exclusively intcrn1ok...-i.1far NOE cros.s
`1x-.1k<; relating protons of CsA with protons of CYP. ]11esc tedi(cid:173)
`niquc.s ;lrc generally applic1hlc \Vifh bin.iry or nu1ltico1nponcnt
`molecular asscn1blics, priniarily in systc1ns with very st;tbk nxcptor·
`dlCctor (0111p!cxcs, and rcprcscnt an ,lttr.ictivt· avenue !Or the tL~c of
`Nl\1 R in conjunction \Vi th projects on dn1g design.
`
`<J.
`
`REFERENCES
`I. J. i:. Burd, Ed., Cilf»JfNlill (Karg.;-r, B.1.1d, 1986).
`2. S. L Sd11cibcr, Sricnu 251, 283 (19<Jl).
`3, H. R. L<x»li cl.,/., lh/J1, l.Jii't~ . ..taa 68, 682 (1985).
`4. Ii. Ke;;.~kr, M. Kii-.:k, '111. Wein, ,\t. Gdukt, ih:J. 73, 1818 (llJ'JO).
`5. R. E. lhrnts.:hum.ichcr, M. \\'. lhrding, J. Rio.-, R. J. Dnlg)';<\ D. \V. Spdd1cr,
`Stinv:e 226, 544 (198-1).
`(>. G. fi\cha, II. \Vinnunn·Li<bokl, }:. Lu1g, T. KidhJh<:r, f. X. S.:hmid, N,irure
`337, 476 (1989); N. T.1bhJ1hi, T. llJ.yaoo, M. Swuki, 1biJ .. 11. 47.l.
`7. A. J. Kokt1kr, M. W. I-hiding, R. E. Hand.schimnchn,J. lm•n~n--.,/. 137, 1054
`(1986); M. Kll'."JJnl!bi, II. ,\h1.11ah, W. Fuji, R. lJ11wni, T. Kouuno, {.
`H.ut<'fi,,f. 171, 4525 (l'J1'i9).
`.
`8. S. \'r'. Mic-hnid;, M. K. IV.v:n, T, J. \\!a11.llt>1, M KJ1p!m, S. L. Sdirdbcr, SriN1u
`252, R36 {1991); J. ,\I. Mr~'rc, D. A. l'nnir, ,\I.}. Fiug_ihbon, J. A_ Thornmn,
`,v.i11m· 351, 248 11991)
`ti_ J)_ \'ln Duin~. H,_ F. St.111(!.icn, ['. ,\. Klrplu,, S. L. &hn:ikr, J.Chrdy,Sdo•.u
`252, SJ9 (1'>91).
`JO. C \'lcb.:r a ~1., llic'4l1""i.<f•)' 30, 65(,J ( 1991 i.
`IJ. S.\\'.l'c\ik11al.,ibiJ.,1>.6575.
`12 K. \\'iithrich, C. Spirzfadcn, K .• \kmmen, 11. Widn1<r, G. \\'i,\a, FE/IS f,,-11. 2R5,
`237 (l<J<Jl).
`13. J. KJJkn a ~I., '''Mutt 353, 276 (1991).
`H. R- M. \\'(ngcr, A•~\'<1j'. Chem. fot. FJ. Er,..;/. 24, 77 (1985).
`15. J. Lrnrt~ I I. K<~1t<r, R. KJ.pt<i11, \\'. i-;, \"ln (i1m,tcl(n,J. CNupul. /li<W 1\fo/. IH:~.
`l, 219 (1987); J. LJ.lltz, 1-1. KN-<kr, Ii. I'. \\'dxr, R. ,\t. Wengu, W. F. \'an
`Gumteren, lJi,'l"-'lpr.tu 29, 1969 (1990).
`16. R. II. Gritf.:y Jml A.G. R<:"dfidd, Q. Rei>. lii.yhy.<. 19, 51 (1987).
`17. S. \\', l'nik, Natun• 332, 865 (1988),
`18. G. Ouing, H. &:nu, G. \V.1.grll:'r, K. \Vlithridi, j. Ma.\'11. RnM. 70, 500 (1986);
`G. Otting .1.ml K. \\'Uthrkh, Q. Re11. UWrJiy;. 23, 3<J (1990); S. \\'. fc-1ik, J. R.
`luly, J, \V. frickson, C. Ah•d·7~1pltc1l), /liNhn11istry 27, 8297 ( 1988); G. \Vida,
`C. \\'dxr, K. Wdthrich,J. Am. Clum. Sr-r. 113, 4676 {19'91).
`19. G. Otting lnJ K. \\'ilthri.:h,J. A1-!\'n. RoN1. 85, 586 (1989); G. \Vi&r, C. \'ldicr,
`R. Tr.ilJ<er, H. \\'idrfK:r, K. \\'iithrich,J. Am. Chem. ,\\x. 112, 9015 (1990).
`
`Rusting of the Lock and Key Model for
`Protein-Ligand Binding
`
`'A'ILLJA,\1 J_h }<>RGENSEN
`
`A 'fOMlC-LE\'El. KN0,\.'1.Efl{:E OF TllE OEOMETRIES OF PRO(cid:173)
`
`tein-!ig<Uld coniplexes h;1s only been ;KcLmiulating .\incc the
`1nid· l 970s. About 50 x·r.1y stnicnircs have now bc1..'ll
`detern1ined tOr peptide5 or proteins hound to cn7,}'n1es or .unibod·
`ics. The tradition;11 notion of rigid lock .utd key comp!e1ne11tarity
`received support from the C;1rl>' and nu1nerous studies of complexes
`of proteolrtic enzynies \\'ith sn1;1il protein inhibitors (I) and fro1n
`the first exa1npk of an antibody-protein con1plcx (2). I·lo\vevcr, the
`idea ha_~ beco1nc increasingly challenged.
`In fact, conforn1ationaJ changes for cnzyn1cs upon JigJnd uptake
`arc \Veil kno,vn and range fron1 n1ode.st loop n1otions to hinge
`bending (J). The prototypi(al case of Mrong binding, strcptavidin-
`
`Dq>Jnrntnt of Chftni~try, Ylle Univcnity, New l-llwn, Cf 06511.
`
`biotin, i11volvt'.S adju~tn1cnts to strcptavidin that include a loop llip
`(4), and the bear hug applied by hu1nan imnn1nodcliciency virus
`type 1 (HIV· I) protease to a peptide inhibitor is a striking exa1npk
`of larg1>sc,l!e do1nain 1notions (5).
`Recently, the dli:cts of binding on ligand stnicturc ha\'C received
`increased ;ittention. Cases of protOund (OntOrniational clunge have
`hecn provided by the detcr1nination nf 1he .'>tructurcs of the inunu·
`nosupprl'ssi\'C agents FK506 and cydo~porin A (C:\A) cornplcxcd
`with their cytosolic binding prorein~ FKBP .1nd l)'clophilin. X·ray
`stn1Cn1n:::,, have lx·i:n reported IOr the tuKornplcxcd dn1!~s and the
`FKBP-FK506 con1plcx (6), and the structure of CsA bound to
`cyclophilin !us bct·n detcnnincd by two groups u~ing multidin1cn·
`.~ional nuclear magnetic resonance (N:V1R) techniques (7).
`Both binding proteins arc pcptidrl·prolrl-ci.~-tM1lS isomer.iscs and
`have been sho\vn to int(·rl"Crc 'vith T cell signaling upon funning
`lernary con1p!cxc.~ \Yi th their respective i1nn1unosupprcs~ivc agents
`and the protein phosphatase c1lcineurin (8). FK506 is a 1nacrocyclic
`organic n1olccu!c \Vith <l critic.\! u:-kcto-hon1oprolyl subunit (upper
`right p.trt of the stnJCturc) tha! acts as a tr.u1sition·st;nc :,,urrogate
`(9), and c~A is a cyclic undeC.lJXptide. Binding leads to sub~tantial
`cord(lrn1atic>nal change fi:Jr FK506, indudi11g cis-trJns ison1erizarion
`
`954
`
`.SCJE1':CE, VOi .. 254
`
`

`
`Aaj)llmycln
`
`FKS06 unbound
`
`FKS06 bound
`
`Cyclospotln A
`
`of the ;unidl· lxind, conco1ni1.1n1 rcposi1ioning of tl1e ho1noprolirn:
`ring, .1nd inw,1nl di\p<l\itinn of the pyr;Ulo\t' 1int~ {top) tow.ud the
`m.Kroi:vde. For <:~A, cht· unbound srn1<:1urt· has esscn1i.1Hv IH·cn
`ruinnl 'in.<.idc out to rc.Kh the bound (oilfl.H111aiion; 1h~ four
`inrr.irnoki.:ular hydrogen bonds <ire Josi, th(' 9,IO·peptide bond
`L~nnH:rizt'S fron1 ti'> to tr an<>, and l\\'0 sets of frJllr side chains switch
`side'.' of lill' 1 ing. These t'X.unpks sho\v th,H flexible lig.uitl'i i:.1n
`;mdt·rgo suh~tanti:tl gconH.'!ric.1/ distortions to achieve ;\ .<.uito1blc
`binding conl(>rn1ation.
`For v.1ric1y, n.uurc h.1<> .1lso provided rapJ1nrtin, an i1nn1unosup(cid:173)
`pn·ss;11H th.tt hinds to FKBP and is c!osdy rel.ired strucrurall)' to
`fK506, p.1nicul,1rly in the Cl -<:14 binding don1ain. ll1c lxiund and
`unlxn111d .<.tnicturcs of r.1p.unyi..·in arc virtu.llly identical, and the
`distonion of FK506 on binding to FKHP ykld.~ ;t binding donuin
`thJt is. .\ll!X'rintpo~:lbk on the r.lp.1n1ydn s1n1cturc (JO). The itnplkit
`grc.ucr prcorg.tniz;ition of r.1p,1n1ycin 1night be thought to provide
`greatly enhanced binding rc:tuiYc to FK506; in fact, it only ;unotuus
`to ot factor of 2 in the binding const:uHs.
`Although tlw.~c cXJ.tnpk-~ arc !itriking1 they .trc not unprt·nxknlcd.
`The binding of Jysozy1ne h)' a F~u frag1ncnt requires negligible
`distortion of either con1poni..'l1t (2). l·lo\\'C\'er, subsequent in\'c.sti(cid:173)
`gJtions sllggcst thu this is not general. (~01nplcxation of the viral
`H1tigcn ncur.uninidasc by <l F~t· fragn1cnt \\'.ts found to lli~placc
`~on1c Cn po.\itions in a binding loop by 1non.' 1han I A fro1n their
`loc:Hion~ in th(' fr.::c cnzyntl' (//),,\,ion.· r<..'<:t·ntly, .u1 x·ray .<.tnicn1rc
`has lxcn tcportcd tOr 3 F .. t. c(101pkx \vith <l 19-·atnino atid hontolog
`of the C helix of n1yolwnwry1hrin (12). Unbound in 'vatt·r, 1he
`pcptitk show~ no .'it.tbk sctond.uy stntcturc, but the Nl·l 2·tcr1ninal
`n:gion of the peptide ft>rn1~ a type II i~ turn when bound to the
`antitxxl)'. Another salient cx.unplc i'> provilkd by the l"Xpul\iOn of
`thl· hrnw froin n1yoglobin upon bindint~ to ;Jn .intibody to :1.pon1yo·
`glohin (LI). Furthcrn1orl', 1hc isol.ul~d S-pcptide of ribonudc.\.\l' A
`•l1'nvs no hclicity Jt 25"C hut rcgJins full hdic.il ch~lr;Ktcr upon
`binding in the S-pro1cin (14). In face, 1no~c sccond:lf)' structure in
`proteins can l)(' con~idcrcd to arise fron1 hindinglikc i1Hl'r,1t.:tions
`with the rc1naintkr of lill' protein.
`
`15 NO\'l'.\\llER 19"'}1
`
`CsA unbound
`
`CsA bound
`
`'ll1c.~c L'xa1nplc.s conlinn the re.lson;1bk expect.llion th.ii flexible
`1no!eculcs distort 10 li)nn optin1al intt.'r.Ktions \\'ith binding part·
`ncrs. A practic:ll con!.t't1uencc is 1hc fru.~tration that \Viii oft<'n
`a.ccon1pany J.tten1p1.<. 10 dl\~ign dn1gs hy an.llogy to rhc strucn1rcs of
`f1l'Xil)k, unbound .Ktivt· subst.1nc(·s.
`
`REl'l',RENCES
`
`I. )). M. Bk.ow, Au. C:km, Ro. 9, HS ( 197b); R. llul-cr .iml \\'. Uo .. k, 1MJ. ll, I l·i
`(1978); S. J, Hubh.1.11!, S. f. C.lrnph::U, J.M. 'lhtnnwn,). ,\f, .. J. lJid. 220, 507
`(19?1).
`2. A. G. 1\mit, R. A. Muiun.i, S. f.,, \'. Phillip•, R. J, l'oljlk., S1U,..a 233, 747
`( 1986).
`.t \\'. S. Hcnn<tt and I{. lluh<r, (.'RC Clir. lfri'. Jli,\thtm. 15, 291 (1 1)84).
`4. I'. C. \\'d'<'r, D. 11. Ohkml<)rf, J. J. \\'cmk>!<nti, l'. R. S.ikn1tn<", S1iou.- 243, 85
`(19l!.9).
`5. M. Millrr ,t J/., iUJ. 2·16, 1149 (1989).
`6 t: D. VM1 Du\uc-, fl. r. ,<;1Jr1<.lie11, f'. A. Kl1r!u,, S. L S..hHih.;;r, J. Chrdy, i!i·l-
`152, 1:09 (!991)
`7. C. \VdJ.Cr o .JI., fli,\"/,1miwr .lO, 6S6.l (l9'Jl); S. W. f,;1k a"'·· ,h,J., p. 657~.
`8. J. l.iu, J. I>. l'lnll<"r, Jr,). Fri(JmJn, I. \\',i~'nun, S. L. Sd1u1bc:t, C:.-1( 66, li()7
`(1991).
`9. M. K. Ros(11, H.. F. ScJndJ~n. t\. Cllu, ,\\. Nlbcwb, S. L S ... hr,ih.:r, Sti<•l(<'
`2·Hl, l\6.l ( 19')()).
`tf. D. V>n Duym·, fl. r Sum.hen, S. l. S..luc1l'\r, J. ChrJy, J. .·111. c/,,·m. s.--<.
`11.~. 74.B \ 19<>1)
`11. J>. M. (t:olrnm .-t .,/., ,v,,,,,,, 326, 35S tl9l\7)
`12. R. I.. StJnJidJ, T. ,\\.Fina, K. A. Lema, I. A \\'1\,,m, Sfiow.·,. 2·t8, 712 (1990).
`!.\. M. J. Crumpton, lli«<li<m.). 100, 223 ( 196(1)
`14. l'. S. Kim, A. I\la1.}u'~.i, It I.. BJ!dwin,}. ,\(,,/.Iii.-/. 162, 187 (l9S2).
`
`10