Tuning Histone Site Selectivity in the Nucleosome with Organometallic Agents

Levy, A.; Adhireksan, Z.; von Erlach, T.; Palermo, G.; Nazarov, A. A.; Hartinger, C. G.; Dyson, P. J.; Rothlisberger, U.; Davey, C. A.

doi:10.1101/2025.11.13.688318

bioRxiv · 10.1101/2025.11.13.688318

Tuning Histone Site Selectivity in the Nucleosome with Organometallic Agents

Levy, A.·Adhireksan, Z.·von Erlach, T.·Palermo, G.·Nazarov, A. A.·Hartinger, C. G.·Dyson, P. J.·Rothlisberger, U.·Davey, C. A.

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Abstract

Platinum anticancer drugs tend to target DNA whereas certain ruthenium and osmium organometallic compounds, including those with known anticancer activity, preferentially bind histone proteins in chromatin. We earlier found that Ru/Os arene 2-pyridinecarbothioamide antitumor agents display unique or partially overlapping profiles of histone protein binding in the nucleosome compared to Ru arene phosphaadamantane (RAPTA) antimetastasis drugs, but the basis for this difference is unclear. Here we structurally characterized the nucleosome binding effects of arene ligand substitutions and carried out a multiscale simulation analysis, which reveals that the interplay between metal cation and non-leaving ligand identity dictates adduct stability and whether complexes target electronegative surface patches, internal crevices, or both. We show that the nucleosome superhelical crevice acts as a small molecule selectivity filter and that multi-site binding profiles can be expanded or reduced through defined ligand substitutions, which modulate dynamic and steric attributes. Our findings suggest new avenues for rationally developing Ru/Os organometallics that could help expand the scope of chromatin-targeting therapeutics. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/688318v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@188bc1dorg.highwire.dtl.DTLVardef@1f619d5org.highwire.dtl.DTLVardef@1a0ebaorg.highwire.dtl.DTLVardef@bd0abb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Levy, A., Adhireksan, Z., von Erlach, T., Palermo, G., Nazarov, A. A., Hartinger, C. G., Dyson, P. J., Rothlisberger, U., Davey, C. A.. 2025-11-14. Tuning Histone Site Selectivity in the Nucleosome with Organometallic Agents. https://doi.org/10.1101/2025.11.13.688318

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