Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms22031496
Keywords
Rh compounds; metal complexes; metallodrugs; protein metalation; dirhodium carboxylates
Funding
- AIRC foundation [22587]
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The study reports the structures of adducts formed by the reaction of the cytotoxic paddlewheel dirhodium complex [Rh-2(mu-O2CCH3)(4)] with the model protein HEWL. The results provide insights into the reactivity of dirhodium tetracarboxylates with proteins, offering valuable information for the design of new Rh-containing biomaterials with potential applications in catalysis or medicinal chemistry. The complex structures shed light on the mechanism of action of these potential anticancer agents.
The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh-2(mu-O2CCH3)(4)] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh-2(mu-O2CCH3)(4)] extensively reacts with HEWL:it in part breaks down, at variance with what happens in reactions with other proteins. A Rh center coordinates the side chains of Arg14 and His15. Dimeric Rh-Rh units with Rh-Rh distances between 2.3 and 2.5 angstrom are bound to the side chains of Asp18, Asp101, Asn93, and Lys96, while a dirhodium unit with a Rh-Rh distance of 3.2-3.4 angstrom binds the C-terminal carboxylate and the side chain of Lys13 at the interface between two symmetry-related molecules. An additional monometallic fragment binds the side chain of Lys33. These data, which are supported by replicated structural determinations, shed light on the reactivity of dirhodium tetracarboxylates with proteins, providing useful information for the design of new Rh-containing biomaterials with an array of potential applications in the field of catalysis or of medicinal chemistry and valuable insight into the mechanism of action of these potential anticancer agents.
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