Gold metalation of proteins: Structural studies

Abstract

Gold compounds have emerged as a novel class of metallodrugs with a promising future in medicinal inorganic chemistry. Despite gold compounds have been intensively investigated for the treatment of many diseases, their mechanism of action is not fully understood at the molecular level. However, the recognition process by proteins is accepted as a key feature for the biological activity of these molecules. This review presents the research performed during the last decade(s) concerning the structural studies on the products of the reactions between gold-based drugs and proteins. A comparative analysis of the structural features of the known gold/protein adducts suggests that several binding mechanisms are possible. It emerges that gold(III) compounds break down before or upon protein binding and that Au(III) reduces to Au(I) during this process. In agreement with the hard and soft acids and bases (HSAB) theory, Au(I) centers prefer thiolates of free Cys side chains; sulfur atoms of Met are less frequently observed, while N atoms of the side chains of His, Lys, Arg and Gln and O atoms of Glu and Asp are also possible Au binding sites. Au can bridge two protein residue side chains (Cys/Cys, Cys/His, Cys/Asp, Cys/Asn, His/His, His/Lys, His/Gln); Au…π interactions can also be formed. The formation of gold/protein adducts does not alter the overall folding of the investigated proteins, but it can modify the active site conformation, inhibiting the enzymatic activity. The process of gold metalation of proteins is selective.