Interfacial water confers transcription factors with dinucleotide specificity

Morgunova, Ekaterina; Nagy, Gabor; Yin, Yimeng; Zhu, Fangjie; Nayak, Sonali Priyadarshini; Xiao, Tianyi; Sokolov, Ilya; Popov, Alexander; Laughton, Charles; Grubmuller, Helmut; Taipale, Jussi

doi:10.1038/s41594-024-01449-6

Interfacial water confers transcription factors with dinucleotide specificity

Morgunova, Ekaterina; Nagy, Gabor; Yin, Yimeng; Zhu, Fangjie; Nayak, Sonali Priyadarshini; Xiao, Tianyi; Sokolov, Ilya; Popov, Alexander; Laughton, Charles; Grubmuller, Helmut; Taipale, Jussi

Authors

Ekaterina Morgunova

Gabor Nagy

Yimeng Yin

Fangjie Zhu

Sonali Priyadarshini Nayak

Tianyi Xiao

Ilya Sokolov

Alexander Popov

Professor CHARLES LAUGHTON CHARLES.LAUGHTON@NOTTINGHAM.AC.UK
PROFESSOR OF COMPUTATIONAL PHARMACEUTICAL SCIENCE

Helmut Grubmuller

Jussi Taipale

Abstract

Transcription factors (TFs) recognize specific bases within their DNA-binding motifs, with each base contributing nearly independently to total binding energy. However, the energetic contributions of particular dinucleotides can deviate strongly from the additive approximation, indicating that some TFs can specifically recognize DNA dinucleotides. Here we solved high-resolution (<1 Å) structures of MYF5 and BARHL2 bound to DNAs containing sets of dinucleotides that have different affinities to the proteins. The dinucleotides were recognized either enthalpically, by an extensive water network that connects the adjacent bases to the TF, or entropically, by a hydrophobic patch that maintained interfacial water mobility. This mechanism confers differential temperature sensitivity to the optimal sites, with implications for thermal regulation of gene expression. Our results uncover the enigma of how TFs can recognize more complex local features than mononucleotides and demonstrate that water-mediated recognition is important for predicting affinities of macromolecules from their sequence.

Citation

Morgunova, E., Nagy, G., Yin, Y., Zhu, F., Nayak, S. P., Xiao, T., Sokolov, I., Popov, A., Laughton, C., Grubmuller, H., & Taipale, J. (2025). Interfacial water confers transcription factors with dinucleotide specificity. Nature Structural and Molecular Biology, https://doi.org/10.1038/s41594-024-01449-6

Journal Article Type	Article
Acceptance Date	Nov 12, 2024
Online Publication Date	Jan 3, 2025
Publication Date	Jan 3, 2025
Deposit Date	Jan 7, 2025
Publicly Available Date	Jan 8, 2025
Journal	Nature Structural & Molecular Biology
Print ISSN	1545-9993
Electronic ISSN	1545-9985
Publisher	Nature Publishing Group
Peer Reviewed	Peer Reviewed
DOI	https://doi.org/10.1038/s41594-024-01449-6
Keywords	DNA; Systems biology; Transcription factors; X-ray crystallography
Public URL	https://nottingham-repository.worktribe.com/output/43800037
Publisher URL	https://www.nature.com/articles/s41594-024-01449-6
Additional Information	Received: 17 October 2023; Accepted: 12 November 2024; First Online: 3 January 2025; : The authors declare no competing interests.

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