Ipattern  paragraph style default tab maximum page size arrow size slide show template name circle old arc rectangle old text block 3D viewer polygon group rounded rect new page image text block arc note page tab count token table current item numberaudio clip old templates encapsulated PS current page numbertemplates version string page image back pointer (This file created by Showcase V2.0.3 dHw TdBD@BDD&D@  Modelling the E-Selectin/s-Le ComplexDD @DD@D@D @  xe E-Selectin/s-Le ComplexBCBCBC@  ?.....CCCCԀD)C  >>?E-Selectin (ELAM-1) is a cell-surface adhesion molecule CCCCD2@C/   >>?It is transiently induced on endothelial cells by cytokinesT CCCCyD8C$   >>?Its counter-ligand is a complex oligosaccharide,  sialyl Lewis-x  CCiCC9DCi   >>?Their interaction helps recruit neutrophils intosites of inflammation T CC!CBDC!  >>?The detailed structure-function relationship is of considerable pharmaceutical interest >>?The detailed structure-function relationship is of considerable pharmaceutical ind BD@BDD&D@  Modelling the E-Selectin/s-Le Complexof considerable pharmaceutical inDD@DD @D@D@  xe E-Selectin/s-Le Complexof considerable pharmaceutical inB|D@B|CD3D@  The Selectins are a group of membrane-attached mosaic proteinsrmaceutical in ?B BB BD(CDA?B B? $CC CCCC CC????CC????CC?@??CC????CC?@???CC??@?CC????CC??@?}hCK %CC,CC CC8 CC ????CC(????CC0?@??CC8????CC8?@???CC0??@?CC(????CC ??@?{CH 'CCCCCC  CC ????CC??@?CC????CC????CC?@???CC????CC?@??CC ??@?zpC( (CC4CC(CC@ CC@????CC8??@?CC0????CC(????CC(?@???CC0????CC8?@??CC@??@?zpC( )CCTCCHCC` CC`????CCX??@?CCP????CCH????CCH?@???CCP????CCX?@??CC`??@?zpC( *CCtCChCC CC????CCx??@?CCp????CCh????CCh?@???CCp????CCx?@??CC??@?zpC( +CCCCCC CC????CC??@?CC????CC????CC?@???CC????CC?@??CC??@?zpC( ,CCCCCC CC????CC??@?CC????CC????CC?@???CC????CC?@??CC??@?zpC( -D CDCD C  D C ????DC??@?DC????D C????D C?@???D C????D C?@??D C ??@?zpC( .D C4DC(D C@ D C@????DC8??@?DC0????D C(????D C(?@???D C0????D C8?@??D C@??@?zpC( /D CTDCHD C` D C`????DCX??@?DCP????D CH????D CH?@???D CP????D CX?@??D C`??@?zpC( 0D CtDChD C D C????DCx??@?DCp????D Ch????D Ch?@???D Cp????D Cx?@??D C??@?zpC( 1D CDCD C D C????DC??@?DC????D C????D C?@???D C????D C?@??D C??@?zpC( 2D CDCD C D C????DC??@?DC????D C????D C?@???D C????D C?@??D C??@?zpC( 3D CDCD C D C????DC??@?DC????D C????D C?@???D C????D C?@??D C??@?zpC( 4D CDCD C D C????DC??@?DC????D C????D C?@???D C????D C?@??D C??@?zpC( 5D CɀDCÀD Cπ D Cπ????DCˀ??@?DCǀ????D CÀ????D CÀ?@???D Cǀ????D Cˀ?@??D Cπ??@?zpC( X6CBCBCBCB?~A-?@~AA-CB?WqP?A?CB?AAff?CB?_ A?AE!CB?AAƘƘ?CX X9CBB`eBCBCB?~A-?@~AA-BB?WqP?A?CB?AAff?CB?_ A?AE!CB?AAƘƘ?CX X:D BD BD BD B?~A-?@~AA-D@B?WqP?A?D B?AAff?D B?_ A?AE!D B?AAƘƘ?CX ;CBCBCCC@?CB? <D CD CD CC?D C? =CCCCCC8B`?CC? >C CDCC@CCH CC@?*???CCD???*?CCD?@*??CCH???*?CCH?@*???CCD??@*?CCD?*???CC@??@*? ?CCCCCC CC?*???CC???*?CC?@*??CC???*?CC?@*???CC??@*?CC?*???CC??@*? @D CDCDC D C?*???DC???*?DC?@*??D C???*?D C?@*???DC??@*?DC?*???D C??@*? ACC8CC8CC@?CC@? BCCCCCC?CC? CD CD CD C?D C? GBCpBACIVC_CqvBCp??@@?BCP?A?A?CCP?AA??CCp?@?A?CC`??@@?CC`?@??xCh HCCCPCPCTCCCC??@@?CC?A?A?CC?AA??CC?@?A?CC??@@?CC?@??xCh IDCDUCثPDXCCDC??@@?DC?A?A?DC?AA??DC?@?A?D C??@@?D C?@??xChJCgCĀCgCCCĀ  CRD are a group of membrane-attached mosaic proteinsrmaceutical inLCoCCoCCC  EGF are a group of membrane-attached mosaic proteinsrmaceutical inMDCDCD+@C  Cys-rich a group of membrane-attached mosaic proteinsrmaceutical inNDCDCD(@C  repeats a group of membrane-attached mosaic proteinsrmaceutical in PCCCCCCCC?AL?L?CC??AL?CC?AL??C QCCCCCCCC?@LA?L?CC??AL?CC?AL??8 SDCDCDC DC?>ݠ@?Ҟ3?DC?@[?D@O?DC?>c?<}DB%?DC??@?DC?Af?>s@?DC??ž?@{Be"R?DC??@@L?DC?Bٙ??ɬCTBCBCzCC  N a group of membrane-attached mosaic proteinsrmaceutical inVCBCBhC4B!  C a group of membrane-attached mosaic proteinsrmaceutical inWABABDBB#  L-Selectin group of membrane-attached mosaic proteinsrmaceutical inXCwBCwB$C܀B%  E-Selectin (ELAM-1)of membrane-attached mosaic proteinsrmaceutical inYDBDBDD,B'  P-Selectin(PADGEM)brane-attached mosaic proteinsrmaceutical indBD @BDDD @)  Modelling the E-Selectin/s-Le Complex mosaic proteinsrmaceutical inCD CDCD +  xe E-Selectin/s-Le Complex mosaic proteinsrmaceutical in\BCBBBC-@  ?......ic proteinsrmaceutical inT??^BCBC̀DC/  >>?The CRD is a member of the C-type animal lectins ,whose sugar binding is calcium dependent>?The CRD is a member of the C-type animal lectins ,whose sugar binding is caT??_BCBCD%@C1  >>?C-type lectin domains are found in several extracellularmosaic proteins in higher animals >?C-type lectin domains are found in several extracellularmosaic proteins in higT??`BCBCD4C3  >>?In 1992 Drickamer's group solved the X-ray crystal structure of the CRD from rat mannose-binding proteinDrickamer's group solved the X-ray crystal structure of the CRD froT??aBCtBCDD@Ct5  >>?This provided the opportunity for the modelling of E-selectin by homology (using COMPOSER)>>?This provided the opportunity for the modelling of E-selectin by homology (usT??bBC.BBD#C.7  >>?More recently the same group published the structureof the rat-MBP complexed with an oligosaccharidely the same group published the structureof the rat-MBP complexed T??cBBBBpD-B9  >>?They also confirmed the details of the calcium-dependentbinding by mutagenesis experiments>>?They also confirmed the details of the calcium-dependentbinding by mutagenesisdBD@BDD$D@;  Modelling the E-Selectin/s-Le Complexum-dependentbinding by mutagenesisCD@CD @D@D@=  xe E-Selectin/s-Le Complexum-dependentbinding by mutagenesisfBCBC BC?@  ?.....um-dependentbinding by mutagenesisT??gBCBCDCA  >>?The collaborative group of Genentech, Glycomed, &Hoffman-LaRoche used mutagenesis and mAbs >>?The collaborative group of Genentech, Glycomed, &Hoffman-LaRoche used mutagenesis aT??hBCBCD@CC  >>?Blocking antibodies and mutations were assessedby their effect on binding assays >>?Blocking antibodies and mutations were assessedby their effect on binding asT??iBCBCDCE  >>?Crucial residues involved in the s-Lex binding wereidentified in their recent publication (Oct '92)ucial residues involved in the s-Lex binding wereidentified in their recentT??jBCsBBDCsG  >>?These were Pro-46, Ser-47, Tyr-48, Arg-97, Lys-99,Lys-111, & Lys-113This constitutes a basic patch about 10 Angstroms from the calcium site& Lys-113dBDBCD DI  Modelling the E-Selectin/s-Le Complexalcium site& Lys-113CDCDCDGK  xe E-Selectin/s-Le Complexalcium site& Lys-113kBCBC0BCM@  ?....xalcium site& Lys-113T??lBCBCD%CO  >>?In MBP the 3'-OH & 4'-OH of mannose were found tobind to the calcium ion and its liganding side-chainshe 3'-OH & 4'-OH of mannose were found tobind to the calcium ion T??mBCBCDCQ  >>?In E-selectin the 2'-OH & 3'-OH of s-Lex fucose could bind similarly  >>?In E-selectin the 2'-OH & 3'-OH of s-Lex fucose could bind similarlyT??nBCBCiDCS  >>?The s-Lex sialic acid carboxylate may then be attracted to the basic patch >>?The s-Lex sialic acid carboxylate may then be attracted to the basic patchT??oBCTBC$D7CTU  >>?The s-Lex ligand was fitted onto the model surface byadjucting glycosidic torsion angles, and tweaking side-chainswas fitted onto the model surface byadjucting glycosidic todBD@BDD$D@W  Modelling the E-Selectin/s-Le Complexsurface byadjucting glycosidic toCD@CD @D@D@ Y  xe E-Selectin/s-Le Complexsurface byadjucting glycosidic topBDBBBD[@  ?......e byadjucting glycosidic to??qBCBCDC]  >>?The model of the complex is speculative  byadjucting glycosidic to??rBCBCD C_  >>?It agrees with the relevant experimental dataadjucting glycosidic to??sBCBCDCa  >>?The gross details are most likely correctadjucting glycosidic to??tBCBCqDCc  >>?It awaits confirmation by X-ray crystallographyadjucting glycosidic to??uBCFBCDCFe  >>?The rational design of anti-inflammatory agentsmay be helpedsidic toT??vBBBBD%Bg  >>?Other people did all the hard work . They are willinglyand gratefully acknowledged. >>?Other people did all the hard work . They are willinglyand gratefully acknodBD@BDD$D@i  Modelling the E-Selectin/s-Le Complexare willinglyand gratefully acknoCD@CD @D@D@k  xe E-Selectin/s-Le Complexare willinglyand gratefully acknodBD@BDD&D@m  Modelling the E-Selectin/s-Le Complexare willinglyand gratefully acknoDD@DD @D@D@no  xe E-Selectin/s-Le Complexare willinglyand gratefully acknod BD@BDD$D@q  Modelling the E-Selectin/s-Le Complexare willinglyand gratefully acknoCD@CD @D@D@s  xe E-Selectin/s-Le Complexare willinglyand gratefully ackno