Probing and Modulating Transcription Factor–DNA Interactions via Chemically Modified Proteins Muhammad Jbara Chemical protein synthesis provides a powerful means to prepare novel, modified proteins with atomic-level precision, offering unprecedented opportunities to understand fundamental biological processes.1 Of particular interest is gene expression, which is controlled through interactions between transcription factors (TFs) and DNA. This presentation will highlight the power of combining total synthesis and late-stage transformations to generate complex, modified proteins for deciphering the molecular roles of post-translational modifications (PTMs) in TFs regulation. Specific examples will focus on the synthesis of site-specifically phosphorylated and acetylated TFs, such as the Myc/Max system.2, 3 Remarkably, these studies revealed that phosphorylation and acetylation patterns modulate Max–DNA interactions by altering DNA binding affinity and sequence specificity. Importantly, such mechanistic insights led to the development of novel bioactive miniproteins derived from Max (μMax), capable of inhibiting oncogene expression and cancer cell proliferation through antagonistic binding to target genes in cancer cells, paving the way for the development of new therapeutic proteins targeting oncogene expression.4-6 Reference 1. O. Harel, M. Jbara, Angew. Chem. Int. Ed., 2023, 62, e202217716 2. R. Nithun, Y. Yao, X. Lin, S. Habiballah, A. Afek, M. Jbara, Angew. Chem. In. Ed., 2023, 62, e202310913 3. R. Nithun, Y. Yao, O. Harel, S. Habiballah, A. Afek, M. Jbara, ACS Central Science, 2024, 10, 1295–1303 4. X. Lin, S. Mandal, R. Nithun, R. Kolla, B. Bouri, H. Lashuel, M. Jbara, JACS, 2024, 146, 25788 5. X. Lin, O. Harel, M. Jbara, Angew. Chem. In. Ed., 2024, 63, e202317511 6. O. Harel, F. Nadal-Bufi, R. Nithun, Y. Yao, A. Afek, M. Vendrell, M. Jbara, JACS, 2025, 147, 46, 42647

Probing and Modulating Transcription Factor–DNA Interactions via Chemically Modified Proteins
Muhammad Jbara
Chemical protein synthesis provides a powerful means to prepare novel, modified proteins with atomic-level precision, offering unprecedented opportunities to understand fundamental biological processes.1 Of particular interest is gene expression, which is controlled through interactions between transcription factors (TFs) and DNA. This presentation will highlight the power of combining total synthesis and late-stage transformations to generate complex, modified proteins for deciphering the molecular roles of post-translational modifications (PTMs) in TFs regulation. Specific examples will focus on the synthesis of site-specifically phosphorylated and acetylated TFs, such as the Myc/Max system.2, 3 Remarkably, these studies revealed that phosphorylation and acetylation patterns modulate Max–DNA interactions by altering DNA binding affinity and sequence specificity. Importantly, such mechanistic insights led to the development of novel bioactive miniproteins derived from Max (μMax), capable of inhibiting oncogene expression and cancer cell proliferation through antagonistic binding to target genes in cancer cells, paving the way for the development of new therapeutic proteins targeting oncogene expression.4-6
Reference
1. O. Harel, M. Jbara, Angew. Chem. Int. Ed., 2023, 62, e202217716
2. R. Nithun, Y. Yao, X. Lin, S. Habiballah, A. Afek, M. Jbara, Angew. Chem. In. Ed., 2023, 62, e202310913
3. R. Nithun, Y. Yao, O. Harel, S. Habiballah, A. Afek, M. Jbara, ACS Central Science, 2024, 10, 1295–1303
4. X. Lin, S. Mandal, R. Nithun, R. Kolla, B. Bouri, H. Lashuel, M. Jbara, JACS, 2024, 146, 25788
5. X. Lin, O. Harel, M. Jbara, Angew. Chem. In. Ed., 2024, 63, e202317511
6. O. Harel, F. Nadal-Bufi, R. Nithun, Y. Yao, A. Afek, M. Vendrell, M. Jbara, JACS, 2025, 147, 46, 42647