Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme

Abstract

The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh2(μ-O2CCH3)4] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh2(μ-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 Å 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 Å 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.

Reactivity of a fluorine-containing dirhodium tetracarboxylate compound with proteins

“…X-ray structure of the adduct with HEWL When [Rh 2 (OAc) 4 ] reacts with HEWL it degrades under a variety of experimental conditions. 24 In crystals of HEWL exposed to [Rh 2 (OAc) 4. ] in 10 mM HEPES at pH 7.5 and 2.00 M sodium formate, monometallic Rh centres are found close to the side chains of Arg14/His15, Lys13 and C-terminal carboxylate, Asp101, Asn93 and Lys96, Lys33.…”

“…in 10 mM HEPES at pH 7.5 and 2.00 M sodium formate, monometallic Rh centres are found close to the side chains of Arg14/His15, Lys13 and C-terminal carboxylate, Asp101, Asn93 and Lys96, Lys33. 24 The structure of HEWL derived from crystals soaked in a solution of [cis-Rh 2 (OAc) 2 (tfa) 2 ] in 10 mM HEPES at pH 7.5 and 2.00 M sodium formate was refined at 1.48 Å resolution. The overall structure of HEWL in this crystal is almost identical to that of metal free protein (Fig.…”

“…Results are compared with those obtained when the same proteins react with [Rh 2 (OAc) 4 ]. 21,24 Methods Materials [Rh 2 (OAc) 4 ], CF 3 COOH (TFA), hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) were purchased from Sigma Chemical Co and used without further purification. All the organic solvents were obtained from VWR (Milan, Italy) or Merck Life Science S.r.l (Milan, Italy) at their highest degree of purity available and were used without further purification.…”

Trends in coordination of rhenium organometallic complexes in the Protein Data Bank

“…In our Forward look as a concluding summary of this review, the question we ask is: what is the best way for this field to progress? Several chemical mechanistic studies have focused on protein-metal coordination and selectivity for rhenium (Zobi & Spingler, 2012;Santoro et al, 2012;Takematsu et al, 2013;Brink & Helliwell, 2019aBinkley et al, 2011), for platinum (Messori & Merlino, 2016;Tanley et al, 2014;Wang et al, 2017) or for rhodium (Loreto et al, 2021;Abe et al, 2009;Daubit et al, 2020). However, protein-ligand (i.e.…”

Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity

“…Structural data have been also collected on adducts formed upon the reaction of a model protein hen egg white lysozyme with the paddlewheel dirhodium tetraacetate complex (Rh 2 (act) 4 , act = acetate) under different experimental conditions [ 23 ]. This compound exhibited in vivo anticancer activity against Ehrlich ascites, L1210 tumors, sarcoma 180 and P388 leukemia [ 24 , 25 , 26 ].…”