Research
Our group develops novel synthetic strategies for preparing complex modified proteins and engineering new analogs for fundamental research and biomedical applications. We focus on proteins associated with cancer and neurodegenerative diseases, such as transcription factors. Our research programs integrate cutting-edge tools from organic and bioorganic chemistry, organometallic chemistry, biochemistry, and chemical biology to create and investigate complex proteins linked to human diseases, laying the groundwork for novel therapeutic modalities.
Chemical Synthesis of Post-Translationally Modified Transcription Factors for Probing Gene Expression Regulation
Transcription factors (TFs) are pivotal proteins responsible for regulating gene expression by interacting with specific DNA sequences to activate or suppress gene transcription. TFs activity is regulated by post-translational modifications (PTMs) that can modulate TF-DNA interactions and impact gene expression. We are interested in understanding how natural transformation affects TFs structure, function, and gene expression by chemically synthesizing site-specifically modified TFs.
Over the past few years, our research group has established powerful synthetic strategies to chemically synthesize full-length Max TF for the first time. The isolation of homogeneous Max analogs bearing defined transformations enabled us to probe and analyze the molecular role of essential PTMs, such as phosphorylation and acetylation, in Max’s function. Remarkably, we generated a library of novel Max variants with distinct modification patterns, including mono- and doubly phosphorylated and acetylated analogs with high precision. Through comprehensive DNA-binding analyses, we discovered that modification site(s) play a crucial role in Max’s DNA-binding activity, highlighting the regulatory significance of PTMs in modulating Max-DNA interactions. Strikingly, our results demonstrate that TF-PTMs not only influence protein-DNA interactions but also modulate sequence specificity, which is pivotal for regulating target gene expression. Our findings provide critical insights into the hidden molecular code governing PTM-modulated TF-DNA interactions, paving the way for a deeper understanding of gene expression regulation and laying the foundation for studying other essential TFs of physiological significance.
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O. Harel and M. Jbara, Molecules, 2022, 27(14), 4389
R. V. Nithun, Y. Minyi Yao, X. Lin, S. Habiballah, A. Afek, and M. Jbara, Angew. Chem. Int. Ed., 62, 2023, e202310913
R. V. Nithun, Y. Minyi Yao, O. Harel, S. Habiballah, A. Afek, M. Jbara, ACS Central Science, 2024, 10, 6, 1295
R. V. Nithun, Shada Khoury, Muhammad Jbara, Org. Lett., 2025
