Crystal Structures of TbCatB and Rhodesain, Potential Chemotherapeutic Targets and Major Cysteine Proteases of Trypanosoma brucei

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dc.contributor.authorKerr, Iain D.en
dc.contributor.authorWu, Pengen
dc.contributor.authorMarion-Tsukamaki, Rachelen
dc.contributor.authorMackey, Zachary B.en
dc.contributor.authorBrinen, Linda S.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2018-06-01T19:05:19Zen
dc.date.available2018-06-01T19:05:19Zen
dc.date.issued2010-06-01en
dc.description.abstractBackground: Trypanosoma brucei is the etiological agent of Human African Trypanosomiasis, an endemic parasitic disease of sub-Saharan Africa. TbCatB and rhodesain are the sole Clan CA papain-like cysteine proteases produced by the parasite during infection of the mammalian host and are implicated in the progression of disease. Of considerable interest is the exploration of these two enzymes as targets for cysteine protease inhibitors that are effective against T. brucei. Methods and Findings: We have determined, by X-ray crystallography, the first reported structure of TbCatB in complex with the cathepsin B selective inhibitor CA074. In addition we report the structure of rhodesain in complex with the vinylsulfone K11002. Conclusions: The mature domain of our TbCatNCA074 structure contains unique features for a cathepsin B-like enzyme including an elongated N-terminus extending 16 residues past the predicted maturation cleavage site. N-terminal Edman sequencing reveals an even longer extension than is observed amongst the ordered portions of the crystal structure. The TbCatNCA074 structure confirms that the occluding loop, which is an essential part of the substrate-binding site, creates a larger prime side pocket in the active site cleft than is found in mammalian cathepsin B-small molecule structures. Our data further highlight enhanced flexibility in the occluding loop main chain and structural deviations from mammalian cathepsin B enzymes that may affect activity and inhibitor design. Comparisons with the rhodesainNK11002 structure highlight key differences that may impact the design of cysteine protease inhibitors as anti-trypanosomal drugs.en
dc.description.versionPublished versionen
dc.format.extent? - ? (9) page(s)en
dc.identifier.doihttps://doi.org/10.1371/journal.pntd.0000701en
dc.identifier.issn1935-2735en
dc.identifier.issue6en
dc.identifier.orcidMackey, ZB [0000-0002-4533-0973]en
dc.identifier.urihttp://hdl.handle.net/10919/83438en
dc.identifier.volume4en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000279341300010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectInfectious Diseasesen
dc.subjectParasitologyen
dc.subjectTropical Medicineen
dc.subjectHUMAN AFRICAN TRYPANOSOMIASISen
dc.subjectEFLORNITHINE COMBINATION THERAPYen
dc.subjectGAMBIENSE SLEEPING SICKNESSen
dc.subjectHOST PROTEIN-DEGRADATIONen
dc.subjectCATHEPSIN-Ben
dc.subjectPLASMODIUM-FALCIPARUMen
dc.subjectOCCLUDING LOOPen
dc.subjectCHAGAS-DISEASEen
dc.subjectRISK-FACTORSen
dc.subjectMOUSE MODELen
dc.titleCrystal Structures of TbCatB and Rhodesain, Potential Chemotherapeutic Targets and Major Cysteine Proteases of Trypanosoma bruceien
dc.title.serialPLoS Neglected Tropical Diseasesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Fralin Affiliated Facultyen

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