DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, Chang-Han | ko |
dc.contributor.author | Park, Kyung-Jin | ko |
dc.contributor.author | Kim, Sang Jick | ko |
dc.contributor.author | Kwon, Ohsuk | ko |
dc.contributor.author | Jeong, Kijun | ko |
dc.contributor.author | Kim, Ayeung | ko |
dc.contributor.author | Kim, Yong-Sung | ko |
dc.date.accessioned | 2013-03-09T22:15:18Z | - |
dc.date.available | 2013-03-09T22:15:18Z | - |
dc.date.created | 2012-02-06 | - |
dc.date.created | 2012-02-06 | - |
dc.date.issued | 2011-08 | - |
dc.identifier.citation | JOURNAL OF MOLECULAR BIOLOGY, v.411, no.1, pp.201 - 219 | - |
dc.identifier.issn | 0022-2836 | - |
dc.identifier.uri | http://hdl.handle.net/10203/97622 | - |
dc.description.abstract | Bivalent or bispecific binding activity of proteins has been mainly achieved by assembling two or more domains in a single molecule. Here we report bivalent/bispecific single-domain proteins based on the kringle domain (KD), which has a cystine knot structural motif and is highly tolerant of sequence modifications. KD has seven loops protruding from the core fold into two largely opposite directions, dubbed loop cluster regions (LCRs) 1 and 2. Mutational analysis of previously isolated agonistic KD variants against human death receptors (DRs) 4 and 5 revealed that they can simultaneously recognize two target molecules of DR4 and/or DR5 via the two independent binding sites of LCR1 and LCR2. Binding loop mapping of yeast-surface-displayed KD mutants identified high-affinity target binding loops in LCR2, which were then grafted into conformationally compatible loops located on the opposite side of LCR1 within the same or different KD variants to generate bivalent/bispecific KD variants against DR4 and/or DR5 with improved affinity. The loop-grafted bivalent/bispecific KD variants showed enhanced cell-death-inducing activity of tumor cells compared with their monovalent/monospecific and bivalent/monospecific counterparts, demonstrating an advantage of bispecific targeting to both DR4 and DR5 over the targeting of only one of the two pro-apoptotic receptors. Our results suggest that the KD with the two independent binding surfaces for target recognition is an appropriate scaffold for the development of bivalency and/or bispecificity by loop grafting on the single domain, which offers a distinct advantage over other protein scaffolds with a single binding surface. (C) 2011 Elsevier Ltd. All rights reserved. | - |
dc.language | English | - |
dc.publisher | ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD | - |
dc.subject | CYSTINE-KNOT MINIPROTEINS | - |
dc.subject | YEAST SURFACE DISPLAY | - |
dc.subject | PLASMINOGEN-ACTIVATOR | - |
dc.subject | FUNCTIONAL-ANALYSIS | - |
dc.subject | CANCER-CELLS | - |
dc.subject | TUMOR-CELLS | - |
dc.subject | IN-VITRO | - |
dc.subject | ANTIBODY | - |
dc.subject | APOPTOSIS | - |
dc.subject | PEPTIDES | - |
dc.title | Generation of Bivalent and Bispecific Kringle Single Domains by Loop Grafting as Potent Agonists against Death Receptors 4 and 5 | - |
dc.type | Article | - |
dc.identifier.wosid | 000293938300015 | - |
dc.identifier.scopusid | 2-s2.0-79960697800 | - |
dc.type.rims | ART | - |
dc.citation.volume | 411 | - |
dc.citation.issue | 1 | - |
dc.citation.beginningpage | 201 | - |
dc.citation.endingpage | 219 | - |
dc.citation.publicationname | JOURNAL OF MOLECULAR BIOLOGY | - |
dc.contributor.localauthor | Jeong, Kijun | - |
dc.contributor.nonIdAuthor | Lee, Chang-Han | - |
dc.contributor.nonIdAuthor | Park, Kyung-Jin | - |
dc.contributor.nonIdAuthor | Kim, Sang Jick | - |
dc.contributor.nonIdAuthor | Kwon, Ohsuk | - |
dc.contributor.nonIdAuthor | Kim, Ayeung | - |
dc.contributor.nonIdAuthor | Kim, Yong-Sung | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordAuthor | protein engineering | - |
dc.subject.keywordAuthor | nonantibody protein scaffold | - |
dc.subject.keywordAuthor | TRAIL receptor | - |
dc.subject.keywordAuthor | cell death | - |
dc.subject.keywordAuthor | yeast surface display | - |
dc.subject.keywordPlus | CYSTINE-KNOT MINIPROTEINS | - |
dc.subject.keywordPlus | YEAST SURFACE DISPLAY | - |
dc.subject.keywordPlus | PLASMINOGEN-ACTIVATOR | - |
dc.subject.keywordPlus | FUNCTIONAL-ANALYSIS | - |
dc.subject.keywordPlus | CANCER-CELLS | - |
dc.subject.keywordPlus | TUMOR-CELLS | - |
dc.subject.keywordPlus | IN-VITRO | - |
dc.subject.keywordPlus | ANTIBODY | - |
dc.subject.keywordPlus | APOPTOSIS | - |
dc.subject.keywordPlus | PEPTIDES | - |
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