Formation of a highly dense tetra-rhenium cluster in a protein crystal and its implications in medical imaging

Abstract

The fact that a protein crystal can serve as a chemical reaction vessel is intrinsically fascinating. That it can produce an electron-dense tetranuclear rhenium cluster compound from a rhenium tricarbonyl tribromo starting compound adds to the fascination. Such a cluster has been synthesized previously in vitro, where it formed under basic conditions. Therefore, its synthesis in a protein crystal grown at pH 4.5 is even more unexpected. The X-ray crystal structures presented here are for the protein hen egg-white lysozyme incubated with a rhenium tricarbonyl tribromo compound for periods of one and two years. These reveal a completed, very well resolved, tetra-rhenium cluster after two years and an intermediate state, where the carbonyl ligands to the rhenium cluster are not yet clearly resolved, after one year. A dense tetranuclear rhenium cluster, and its technetium form, offer enhanced contrast in medical imaging. Stimulated by these crystallography results, the unusual formation of such a species directly in an in vivo situation has been considered. It offers a new option for medical imaging compounds, particularly when considering the application of the pre-formed tetranuclear cluster, suggesting that it may be suitable for medical diagnosis because of its stability, preference of formation and biological compatibility.

Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme

“…The C-terminal tail has been previously found to be involved in the recognition of metal centers in the structure of the Ru/HEWL adducts formed upon reaction of the protein with CORM-2 (Ru 2 Cl 4 (CO) 6 ) solved by Ueno and coworkers [ 38 ] and in the structure of the HEWL adduct with a Re compound solved by Helliwell and coworkers [ 50 ]. In the former structure, two Ru centers are close to each other, as in the Rh/HEWL adduct here determined, but the two Ru centers have occupancy < 0.5 (0.30 and 0.50, respectively).…”

“…In the former structure, two Ru centers are close to each other, as in the Rh/HEWL adduct here determined, but the two Ru centers have occupancy < 0.5 (0.30 and 0.50, respectively). In the latter, Re atoms (occupancy 0.39 and 0.55) are bound to the carboxylate oxygens with a Re–O distance of 2.1 and 2.7 Å [ 50 ].…”

“…Interestingly, Asp18 has been already found to be involved in the interaction with metal centers in the structure of other adducts with metal compounds [ 38 , 39 , 50 , 51 , 52 ].…”

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

“…In our research, we have firstly identified that there are more amino-acid types binding to rhenium organometallics than previously seen. Secondly, via our most recent research, we have expanded the available repertoire of rhenium compounds to include multi-metal-centre complexes (Brink & Helliwell, 2017, 2019a. Both these advances have the potential to increase the absorption of the organometallic complex at the organ being imaged.…”

“…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.…”