Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction
Abstract The transcription factor c-Myb promotes the proliferation of hematopoietic cells by interacting with the KIX domain of CREB-binding protein; however, its aberrant expression causes leukemia. Therefore, inhibitors of the c-Myb–KIX interaction are potentially useful as antitumor drugs. Since...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-04497-w |
| _version_ | 1798025256749760512 |
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| author | Shunji Suetaka Yoshiki Oka Tomoko Kunihara Yuuki Hayashi Munehito Arai |
| author_facet | Shunji Suetaka Yoshiki Oka Tomoko Kunihara Yuuki Hayashi Munehito Arai |
| author_sort | Shunji Suetaka |
| collection | DOAJ |
| description | Abstract The transcription factor c-Myb promotes the proliferation of hematopoietic cells by interacting with the KIX domain of CREB-binding protein; however, its aberrant expression causes leukemia. Therefore, inhibitors of the c-Myb–KIX interaction are potentially useful as antitumor drugs. Since the intrinsically disordered transactivation domain (TAD) of c-Myb binds KIX via a conformational selection mechanism where helix formation precedes binding, stabilizing the helical structure of c-Myb TAD is expected to increase the KIX-binding affinity. Here, to develop an inhibitor of the c-Myb–KIX interaction, we designed mutants of the c-Myb TAD peptide fragment where the helical structure is stabilized, based on theoretical predictions using AGADIR. Three of the four initially designed peptides each had a different Lys-to-Arg substitution on the helix surface opposite the KIX-binding interface. Furthermore, the triple mutant with three Lys-to-Arg substitutions, named RRR, showed a high helical propensity and achieved three-fold higher affinity to KIX than the wild-type TAD with a dissociation constant of 80 nM. Moreover, the RRR inhibitor efficiently competed out the c-Myb–KIX interaction. These results suggest that stabilizing the helical structure based on theoretical predictions, especially by conservative Lys-to-Arg substitutions, is a simple and useful strategy for designing helical peptide inhibitors of protein–protein interactions. |
| first_indexed | 2024-04-11T18:15:48Z |
| format | Article |
| id | doaj.art-e9669574a85f447f87f0853676ccf7f8 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T18:15:48Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e9669574a85f447f87f0853676ccf7f82022-12-22T04:09:54ZengNature PortfolioScientific Reports2045-23222022-01-0112111110.1038/s41598-021-04497-wRational design of a helical peptide inhibitor targeting c-Myb–KIX interactionShunji Suetaka0Yoshiki Oka1Tomoko Kunihara2Yuuki Hayashi3Munehito Arai4Department of Life Sciences, Graduate School of Arts and Sciences, The University of TokyoDepartment of Life Sciences, Graduate School of Arts and Sciences, The University of TokyoDepartment of Life Sciences, Graduate School of Arts and Sciences, The University of TokyoDepartment of Life Sciences, Graduate School of Arts and Sciences, The University of TokyoDepartment of Life Sciences, Graduate School of Arts and Sciences, The University of TokyoAbstract The transcription factor c-Myb promotes the proliferation of hematopoietic cells by interacting with the KIX domain of CREB-binding protein; however, its aberrant expression causes leukemia. Therefore, inhibitors of the c-Myb–KIX interaction are potentially useful as antitumor drugs. Since the intrinsically disordered transactivation domain (TAD) of c-Myb binds KIX via a conformational selection mechanism where helix formation precedes binding, stabilizing the helical structure of c-Myb TAD is expected to increase the KIX-binding affinity. Here, to develop an inhibitor of the c-Myb–KIX interaction, we designed mutants of the c-Myb TAD peptide fragment where the helical structure is stabilized, based on theoretical predictions using AGADIR. Three of the four initially designed peptides each had a different Lys-to-Arg substitution on the helix surface opposite the KIX-binding interface. Furthermore, the triple mutant with three Lys-to-Arg substitutions, named RRR, showed a high helical propensity and achieved three-fold higher affinity to KIX than the wild-type TAD with a dissociation constant of 80 nM. Moreover, the RRR inhibitor efficiently competed out the c-Myb–KIX interaction. These results suggest that stabilizing the helical structure based on theoretical predictions, especially by conservative Lys-to-Arg substitutions, is a simple and useful strategy for designing helical peptide inhibitors of protein–protein interactions.https://doi.org/10.1038/s41598-021-04497-w |
| spellingShingle | Shunji Suetaka Yoshiki Oka Tomoko Kunihara Yuuki Hayashi Munehito Arai Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction Scientific Reports |
| title | Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction |
| title_full | Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction |
| title_fullStr | Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction |
| title_full_unstemmed | Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction |
| title_short | Rational design of a helical peptide inhibitor targeting c-Myb–KIX interaction |
| title_sort | rational design of a helical peptide inhibitor targeting c myb kix interaction |
| url | https://doi.org/10.1038/s41598-021-04497-w |
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