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dc.contributor.authorvan der Sloot, A. M.
dc.contributor.authorTur, V.
dc.contributor.authorSzegezdi, E.
dc.contributor.authorMullally, M. M.
dc.contributor.authorCool, R. H.
dc.contributor.authorSamali, A.
dc.contributor.authorSerrano, L.
dc.contributor.authorQuax, W. J.
dc.date.accessioned2018-08-24T08:26:35Z
dc.date.available2018-08-24T08:26:35Z
dc.date.issued2006-05-26
dc.identifier.citationvan der Sloot, A. M. Tur, V.; Szegezdi, E.; Mullally, M. M.; Cool, R. H.; Samali, A.; Serrano, L.; Quax, W. J. (2006). Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the dr5 receptor. Proceedings of the National Academy of Sciences 103 (23), 8634-8639
dc.identifier.issn0027-8424,1091-6490
dc.identifier.urihttp://hdl.handle.net/10379/9954
dc.description.abstractTumor necrosis factor-related apoptosis-inclucing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors (DcR1, DcR2, and osteoprotegerin receptor) that cannot induce apoptosis. The occurrence of DR5-responsive tumor cells indicates that a DR5 receptor-specific TRAIL variant will permit tumor-selective therapies. By using the automatic design algorithm FOLD-X, we successfully generated DR5-selective TRAIL variants. These variants do not induce apoptosis in DR4-responsive cell lines but show a large increase in biological activity in DR5-responsive cancer cell lines. Even wild-type TRAIL-insensitive ovarian cancer cell lines could be brought into apoptosis. In addition, our results demonstrate that there is no requirement for anti body-mediated cross-linking or membrane-bound TRAIL to induce apoptosis through DRS.
dc.publisherProceedings of the National Academy of Sciences
dc.relation.ispartofProceedings of the National Academy of Sciences
dc.subjectcomputational protein design
dc.subjectreceptor selectivity
dc.subjectbiopharmaceutical
dc.subjectdeath receptor
dc.subjectapoptosis-inducing ligand 2
dc.subjectcomputational redesign
dc.subjectmonoclonal-antibodies
dc.subjectcrystal-structure
dc.subjecttrail
dc.subjectdeath
dc.subjectspecificity
dc.subjectapo2l/trail
dc.subjectcomplex
dc.subjectprotein
dc.subjectactivation
dc.titleDesigned tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the dr5 receptor
dc.typeArticle
dc.identifier.doi10.1073/pnas.0510187103
dc.local.publishedsourcehttp://www.pnas.org/content/103/23/8634.full.pdf
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