Ruthenium metalation of proteins: the X-ray structure of the complex formed between NAMI-A and hen egg white lysozyme.

A crystallographic study of the adduct formed between hen egg white lysozyme (HEWL) and NAMI-A, an established ruthenium(iii) anticancer agent in clinical trials, is presented here. The X-ray structure reveals that NAMI-A coordinates the protein, as a naked ruthenium ion, at two distinct sites (namely Asp101 or Asp119) after releasing all its original ligands (DMSO, imidazole and Cl-). Structural data of the HEWL/NAMI-A adduct are compared with those previously obtained for the HEWL adduct of AziRu, a NAMI-A analogue bearing a pyridine in place of imidazole. The present results further support the view that NAMI-A exerts its biological effects acting as a classical "prodrug" first undergoing activation and then causing extensive metalation of relevant protein targets. It is also proposed that the original Ru-ligands, although absent in the final adduct, play a major role in directing the ruthenium center to its ultimate anchoring site on the protein surface.