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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Formation of a highly dense tetra-rhenium cluster in a protein crystal and its implications in medical imaging Alice Brink , John Helliwell Iucrj 6 DOI: 10.1107/S2052252519006651 Open Access Show Abstract ▼ 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.	Jul 2019
I04-Macromolecular Crystallography	New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents Alice Brink , John R. Helliwell Iucrj 4 DOI: 10.1107/S2052252517003475 Diamond Proposal Number(s): [8997] Open Access Show Abstract ▼ Abstract: Multiple possibilities for the coordination of fac-[Re(CO)3(H2O)3]+ to a protein have been determined and include binding to Asp, Glu, Arg and His amino-acid residues as well as to the C-terminal carboxylate in the vicinity of Leu and Pro. The large number of rhenium metal complex binding sites that have been identified on specific residues thereby allow increased target identification for the design of future radiopharmaceuticals. The core experimental concept involved the use of state-of-art tuneable synchrotron radiation at the Diamond Light Source to optimize the rhenium anomalous dispersion signal to a large value (f′′ of 12.1 electrons) at its LI absorption edge with a selected X-ray wavelength of 0.9763 Å. At the Cu Kα X-ray wavelength (1.5418 Å) the f′′ for rhenium is 5.9 electrons. The expected peak-height increase owing to the optimization of the Re f′′ was therefore 2.1. This X-ray wavelength tuning methodology thereby showed the lower occupancy rhenium binding sites as well as the occupancies of the higher occupancy rhenium binding sites.	May 2017
I04-Macromolecular Crystallography	Time-series analysis of rhenium(I) organometallic covalent binding to a model protein for drug development Francois J. F. Jacobs , John R. Helliwell , Alice Brink Iucrj 11 DOI: 10.1107/S2052252524002598 Diamond Proposal Number(s): [28402] Open Access Show Abstract ▼ Abstract: Metal-based complexes with their unique chemical properties, including multiple oxidation states, radio-nuclear capabilities and various coordination geometries yield value as potential pharmaceuticals. Understanding the interactions between metals and biological systems will prove key for site-specific coordination of new metal-based lead compounds. This study merges the concepts of target coordination with fragment-based drug methodologies, supported by varying the anomalous scattering of rhenium along with infrared spectroscopy, and has identified rhenium metal sites bound covalently with two amino acid types within the model protein. A time-based series of lysozyme-rhenium-imidazole (HEWL-Re-Imi) crystals was analysed systematically over a span of 38 weeks. The main rhenium covalent coordination is observed at His15, Asp101 and Asp119. Weak (i.e. noncovalent) interactions are observed at other aspartic, asparagine, proline, tyrosine and tryptophan side chains. Detailed bond distance comparisons, including precision estimates, are reported, utilizing the diffraction precision index supplemented with small-molecule data from the Cambridge Structural Database. Key findings include changes in the protein structure induced at the rhenium metal binding site, not observed in similar metal-free structures. The binding sites are typically found along the solvent-channel-accessible protein surface. The three primary covalent metal binding sites are consistent throughout the time series, whereas binding to neighbouring amino acid residues changes through the time series. Co-crystallization was used, consistently yielding crystals four days after setup. After crystal formation, soaking of the compound into the crystal over 38 weeks is continued and explains these structural adjustments. It is the covalent bond stability at the three sites, their proximity to the solvent channel and the movement of residues to accommodate the metal that are important, and may prove useful for future radiopharmaceutical development including target modification.	May 2024
I04-1-Macromolecular Crystallography (fixed wavelength)	Trends in coordination of rhenium organometallic complexes in the Protein Data Bank Alice Brink , Francois J. F. Jacobs , John R. Helliwell Iucrj 9, 180 - 193 DOI: 10.1107/S2052252522000665 Diamond Proposal Number(s): [8997] Open Access Show Abstract ▼ Abstract: Radiopharmaceutical development has similar overall characteristics to any biomedical drug development requiring a compound's stability, aqueous solubility and selectivity to a specific disease site. However, organometallic complexes containing 188/186Re or 99mTc involve a d-block transition-metal radioactive isotope and therefore bring additional factors such as metal oxidation states, isotope purity and half life into play. This topical review is focused on the development of radiopharmaceuticals containing the radioisotopes of rhenium and technetium and, therefore, on the occurrence of these organometallic complexes in protein structures in the Worldwide Protein Data Bank (wwPDB). The purpose of incorporating the group 7 transition metals of rhenium/technetium in the protein and the reasons for study by protein crystallography are described, as certain PDB studies were not aimed at drug development. Technetium is used as a medical diagnostic agent and involves the 99mTc isotope which decays to release gamma radiation, thereby employed for its use in gamma imaging. Due to the periodic relationship among group 7 transition metals, the coordination chemistry of rhenium is similar (but not identical) to that of technetium. The types of reactions the potential model radiopharmaceutical would prefer to partake in, and by extension knowing which proteins and biomolecules the compound would react with in vivo, are needed. Crystallography studies, both small molecule and macromolecular, are a key aspect in understanding chemical coordination. Analyses of bonding modes, coordination to particular residues and crystallization conditions are presented. In our Forward look as a concluding summary of this topical review, the question we ask is: what is the best way for this field to progress?	Mar 2022

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