title: Ruthenium metalation of proteins: the X-ray structure of the complex formed between NAMI-A and hen egg white lysozyme.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Florence, Florence, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Antonello
authors.initials: A
authors.lastname: Merlino
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D009113:Muramidase / Q000737:chemistry* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry; D017975:Ruthenium Compounds; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; C421864:hen egg lysozyme; D009113:Muramidase; D004121:Dimethyl Sulfoxide